VCV000422846.4 - ClinVar

NM_000070.3(CAPN3):c.46G>A (p.Glu16Lys)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000070.3(CAPN3):c.46G>A (p.Glu16Lys)

Variation ID: 422846 Accession: VCV000422846.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q15.1 15: 42359851 (GRCh38) [ NCBI UCSC ] 15: 42652049 (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	Apr 29, 2017	Aug 11, 2024	May 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000070.3:c.46G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000061.1:p.Glu16Lys	missense
NM_024344.2:c.46G>A	NP_077320.1:p.Glu16Lys	missense
NM_173087.2:c.46G>A	NP_775110.1:p.Glu16Lys	missense
NC_000015.10:g.42359851G>A
NC_000015.9:g.42652049G>A
NG_008660.1:g.16749G>A
LRG_849:g.16749G>A
LRG_849t1:c.46G>A	LRG_849p1:p.Glu16Lys

... more HGVS ... less HGVS

Protein change

E16K

Other names

Canonical SPDI

NC_000015.10:42359850:G:A

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.

The Genome Aggregation Database (gnomAD) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00006

Links

ClinGen: CA7510838 dbSNP: rs772580081 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.
CAPN3		-	-	GRCh38 GRCh37	1739	1881

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	Uncertain significance (1)	criteria provided, single submitter	Dec 13, 2016	RCV000479855.1
Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (1)	no assertion criteria provided	Oct 28, 2019	RCV001835820.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	May 24, 2024	RCV004609399.1

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.
Uncertain significance (Dec 13, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000572417.3 First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017	Comment: The E16K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E16K … (more) The E16K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E16K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with LGMD2A (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. (less)
Uncertain significance (May 24, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005097168.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: The c.46G>A (p.E16K) alteration is located in exon 1 (coding exon 1) of the CAPN3 gene. This alteration results from a G to A substitution … (more) The c.46G>A (p.E16K) alteration is located in exon 1 (coding exon 1) of the CAPN3 gene. This alteration results from a G to A substitution at nucleotide position 46, causing the glutamic acid (E) at amino acid position 16 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Oct 28, 2019)	no assertion criteria provided Method: clinical testing	Limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094425.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

The E16K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E16K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with LGMD2A (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.

Comment:

The c.46G>A (p.E16K) alteration is located in exon 1 (coding exon 1) of the CAPN3 gene. This alteration results from a G to A substitution at nucleotide position 46, causing the glutamic acid (E) at amino acid position 16 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs772580081 ...

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 Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_000070.3(CAPN3):c.46G>A (p.Glu16Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs772580081 ...