VCV000582241.12 - ClinVar

NM_004064.5(CDKN1B):c.482C>T (p.Ser161Phe)

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.

(5)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004064.5(CDKN1B):c.482C>T (p.Ser161Phe)

Variation ID: 582241 Accession: VCV000582241.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.1 12: 12718831 (GRCh38) [ NCBI UCSC ] 12: 12871765 (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	Oct 10, 2018	Oct 26, 2024	Feb 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004064.5:c.482C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004055.1:p.Ser161Phe	missense
NC_000012.12:g.12718831C>T
NC_000012.11:g.12871765C>T
NG_016341.1:g.6464C>T

Protein change

S161F

Other names

Canonical SPDI

NC_000012.12:12718830:C:T

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.

0.00020 (G)

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

Links

dbSNP: rs373917399 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.
CDKN1B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	938	989

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.
Multiple endocrine neoplasia type 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 25, 2024	RCV000706260.7
Hereditary cancer-predisposing syndrome	Likely benign (1)	criteria provided, single submitter	Nov 23, 2022	RCV001023121.4
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 14, 2023	RCV003478447.2

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 (May 26, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004220761.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, … (more) To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0002 (7/34564 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Jan 26, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple endocrine neoplasia type 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000835300.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 161 of the CDKN1B protein (p.Ser161Phe). … (more) This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 161 of the CDKN1B protein (p.Ser161Phe). This variant is present in population databases (rs373917399, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CDKN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 582241). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely benign (Nov 23, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001184948.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Feb 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia type 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005060211.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Dec 14, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005378697.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)

Comment:

To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0002 (7/34564 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 161 of the CDKN1B protein (p.Ser161Phe). This variant is present in population databases (rs373917399, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CDKN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 582241). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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 rs373917399 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_004064.5(CDKN1B):c.482C>T (p.Ser161Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs373917399 ...