VCV000265689.20 - ClinVar

NM_013275.6(ANKRD11):c.2175_2178del (p.Asn725fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_013275.6(ANKRD11):c.2175_2178del (p.Asn725fs)

Variation ID: 265689 Accession: VCV000265689.20

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: 16q24.3 16: 89284364-89284367 (GRCh38) [ NCBI UCSC ] 16: 89350772-89350775 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 8, 2017	Mar 5, 2024	Apr 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_013275.6:c.2175_2178del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037407.4:p.Asn725fs	frameshift
NM_001256182.1:c.2175_2178del
NM_001256182.2:c.2175_2178del	NP_001243111.1:p.Asn725fs	frameshift
NM_001256183.2:c.2175_2178del	NP_001243112.1:p.Asn725fs	frameshift
NM_013275.5:c.2175_2178delCAAA
NC_000016.10:g.89284365TTGT[1]
NC_000016.9:g.89350773TTGT[1]
NG_032003.2:g.211191CAAA[1]

... more HGVS ... less HGVS

Protein change

N725fs

Other names

Canonical SPDI

NC_000016.10:89284363:TTTGTTTGT:TTTGT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10588634 dbSNP: rs886039734 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ANKRD11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2527	2697

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 13, 2022	RCV000255546.9
KBG syndrome	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Apr 19, 2023	RCV000505196.19

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 27, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511350.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322685.10 First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31332282, 34971082, 25363768, 28191890, 27824329, 32124548, 31981491, 33917340) (less)
Pathogenic (Mar 13, 2018)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	KBG syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001149681.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: female Tissue: blood
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440903.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Jan 02, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001519851.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (1) PubMed: 27824329 Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 27824329]
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: de novo	Genome Medicine, Institute for Basic Research in Developmental Disabilities Accession: SCV002562752.2 First in ClinVar: Aug 23, 2022 Last updated: Sep 03, 2022	Publications: PubMed (1) PubMed: 35970914 Comment: KBG syndrome Number of individuals with the variant: 1
Pathogenic (Jun 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003808048.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated, PM6 moderated Number of individuals with the variant: 1 Clinical Features: Neonatal asphyxia (present) , Cat cry (present) , Neurodevelopmental delay (present) , Neonatal respiratory distress (present) , Primary microcephaly (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: unknown	3billion Accession: SCV003841819.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000265689). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Global developmental delay (present) , Myoclonic-astatic epilepsy (present) , Sensorineural hearing loss disorder (present) , Microcephaly (present) , Vesicoureteral reflux (present) , Low-set ears (present) … (more) Global developmental delay (present) , Myoclonic-astatic epilepsy (present) , Sensorineural hearing loss disorder (present) , Microcephaly (present) , Vesicoureteral reflux (present) , Low-set ears (present) , Overfolded helix (present) , Pes planus (present) , Hirsutism (present) (less)
Pathogenic (Apr 19, 2023)	criteria provided, single submitter (Hauer et al. (Genet Med. 2018)) Method: clinical testing	KBG syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Accession: SCV003918208.1 First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023	Comment: This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 Number of individuals with the variant: 1
Pathogenic (Nov 30, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	KBG syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000833241.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 21782149‚ 25413698‚ 27824329 Comment: For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25413698). This variant has … (more) For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25413698). This variant has been reported to be de novo in an individual affected with autism spectrum disorder (PMID: 27824329). ClinVar contains an entry for this variant (Variation ID: 265689). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn725Lysfs*23) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: de novo	Molecular Genetics Lab, CHRU Brest Accession: SCV004697727.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024
Pathogenic (May 11, 2016)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	KBG syndrome Affected status: yes Allele origin: de novo	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000599241.1 First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797390.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957485.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31332282, 34971082, 25363768, 28191890, 27824329, 32124548, 31981491, 33917340)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000265689). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25413698). This variant has been reported to be de novo in an individual affected with autism spectrum disorder (PMID: 27824329). ClinVar contains an entry for this variant (Variation ID: 265689). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn725Lysfs*23) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients.	Guo L	European journal of human genetics : EJHG	2022	PMID: 35970914
De novo genic mutations among a Chinese autism spectrum disorder cohort.	Wang T	Nature communications	2016	PMID: 27824329
Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.	Walz K	Human genetics	2015	PMID: 25413698
Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia.	Sirmaci A	American journal of human genetics	2011	PMID: 21782149

Text-mined citations for rs886039734 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_013275.6(ANKRD11):c.2175_2178del (p.Asn725fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039734 ...