VCV002663991.2 - ClinVar

NM_030662.4(MAP2K2):c.903dup (p.Gly302fs)

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.

(2)

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_030662.4(MAP2K2):c.903dup (p.Gly302fs)

Variation ID: 2663991 Accession: VCV002663991.2

Type and length

Duplication, 1 bp

Location

Cytogenetic: 19p13.3 19: 4099216-4099217 (GRCh38) [ NCBI UCSC ] 19: 4099214-4099215 (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	Dec 2, 2023	Feb 14, 2024	Oct 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_030662.4:c.903dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_109587.1:p.Gly302fs	frameshift
NM_030662.3:c.903dup		frameshift
NC_000019.10:g.4099222dup
NC_000019.9:g.4099220dup
NG_007996.1:g.29912dup
LRG_750:g.29912dup
LRG_750t1:c.898dup	LRG_750p1:p.Gly302Argfs

... more HGVS ... less HGVS

Protein change

G302fs

Other names

Canonical SPDI

NC_000019.10:4099216:GGGGGG:GGGGGGG

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

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.
Cardiofaciocutaneous syndrome 4	Uncertain significance (1)	criteria provided, single submitter	Oct 18, 2023	RCV003444453.1
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 29, 2023	RCV003539492.2

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 (Oct 18, 2023)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Cardiofaciocutaneous syndrome 4 Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV004171500.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Comment: The MAP2K2 c.903dup (p.Gly302ArgfsTer11) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to … (more) The MAP2K2 c.903dup (p.Gly302ArgfsTer11) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay, however loss-of-function has not been established as a mechanism of disease. To our knowledge, this variant has not been reported in individuals with cardiofaciocutanous syndrome. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.?? (less)
Uncertain significance (Sep 29, 2023)	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: SCV004266173.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This sequence change creates a premature translational stop signal (p.Gly302Argfs11) in the MAP2K2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gly302Argfs11) in the MAP2K2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MAP2K2 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. 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)

Comment:

The MAP2K2 c.903dup (p.Gly302ArgfsTer11) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay, however loss-of-function has not been established as a mechanism of disease. To our knowledge, this variant has not been reported in individuals with cardiofaciocutanous syndrome. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.??

Comment:

This sequence change creates a premature translational stop signal (p.Gly302Argfs*11) in the MAP2K2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MAP2K2 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. 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.

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 this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_030662.4(MAP2K2):c.903dup (p.Gly302fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...