VCV000040770.28 - ClinVar

NM_030662.4(MAP2K2):c.192C>T (p.Val64=)

Germline

Top reviewed classifications are shown here.

Submission summary:

8 submissions

8 submitters

5 conditions

Reviewed by expert panel

Benign

May 2017 by ClinGen RASopa… FDA Recognized Database

for Noonan syndrome and Noonan-related syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_030662.4(MAP2K2):c.192C>T (p.Val64=)

Variation ID: 40770 Accession: VCV000040770.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 4117530 (GRCh38) [ NCBI UCSC ] 19: 4117528 (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 2, 2016	Sep 29, 2024	May 9, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_030662.4:c.192C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_109587.1:p.Val64=	synonymous
NC_000019.10:g.4117530G>A
NC_000019.9:g.4117528G>A
NG_007996.1:g.11599C>T
LRG_750:g.11599C>T
LRG_750t1:c.192C>T	LRG_750p1:p.Val64=

... more HGVS ... less HGVS

Protein change

Other names

p.V64V
NM_030662.3(MAP2K2):c.192C>T

Canonical SPDI

NC_000019.10:4117529: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.

0.05831 (A)

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

1000 Genomes Project 30x 0.05778

1000 Genomes Project 0.05831

The Genome Aggregation Database (gnomAD), exomes 0.05948

Trans-Omics for Precision Medicine (TOPMed) 0.06140

Exome Aggregation Consortium (ExAC) 0.06190

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.06312

The Genome Aggregation Database (gnomAD) 0.06496

Links

ClinGen: CA137916 dbSNP: rs8157 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.
MAP2K2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	782	863

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.
RASopathy	Benign (2)	reviewed by expert panel	May 9, 2017	RCV000473659.14
Cardiofaciocutaneous syndrome 4	Benign (1)	criteria provided, single submitter	Nov 22, 2023	RCV000999991.13
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Apr 17, 2019	RCV002408500.2
not provided	Benign (1)	criteria provided, single submitter	-	RCV004716914.1
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	May 11, 2015	RCV000039473.11

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.
Benign (May 09, 2017)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1) Method: curation	Noonan syndrome and Noonan-related syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616588.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf89340c-b64c-46a6-aef4-094850f57f25 Comment: The filtering allele frequency of the c.192C>T (p.Val64=) variant in the MAP2K2 gene is 7.417% (1283/16512) of South Asian chromosomes by the Exome Aggregation Consortium, … (more) The filtering allele frequency of the c.192C>T (p.Val64=) variant in the MAP2K2 gene is 7.417% (1283/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000314684.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Nov 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Cardiofaciocutaneous syndrome 4 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885671.7 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
Benign (May 11, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000513518.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Aug 18, 2008)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000063158.5 First in ClinVar: May 03, 2013 Last updated: Mar 08, 2017	Number of individuals with the variant: 360
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000561665.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024
Benign (Apr 17, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002720979.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005309552.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024

Comment:

The filtering allele frequency of the c.192C>T (p.Val64=) variant in the MAP2K2 gene is 7.417% (1283/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as 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

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/cf89340c-b64c-46a6-aef4-094850f57f25	-	-	-	-

Text-mined citations for rs8157 ...

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_030662.4(MAP2K2):c.192C>T (p.Val64=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs8157 ...