NM_030662.4(MAP2K2):c.919+4C>T AND RASopathy

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jul 25, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001030072.13

Allele description [Variation Report for NM_030662.4(MAP2K2):c.919+4C>T]

NM_030662.4(MAP2K2):c.919+4C>T

Gene:

MAP2K2:mitogen-activated protein kinase kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_030662.4(MAP2K2):c.919+4C>T

HGVS:

NC_000019.10:g.4099197G>A
NG_007996.1:g.29932C>T
NM_030662.4:c.919+4C>TMANE SELECT
LRG_750t1:c.919+4C>T
LRG_750:g.29932C>T
NC_000019.9:g.4099195G>A
NC_000019.9:g.4099195G>A
NM_030662.3(MAP2K2):c.919+4C>T
NM_030662.3:c.919+4C>T

Links:

dbSNP: rs763424788

NCBI 1000 Genomes Browser:

rs763424788

Molecular consequence:

NM_030662.4:c.919+4C>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001192860	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Likely benign (Jul 25, 2019)	germline	curation	Citation Link,
SCV002177277	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001192860

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Likely benign
(Jul 25, 2019)

germline

curation

Citation Link,

SCV002177277

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 28, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV001192860.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The variant c.919+4C>T is an intronic variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Also, computational prediction tools and conservation analysis suggests that the variant does not impact the protein (BP4). In summary, the clinical significance of the c.919+4C>T variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4, BP7.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002177277.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change falls in intron 7 of the MAP2K2 gene. It does not directly change the encoded amino acid sequence of the MAP2K2 protein. It affects a nucleotide within the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 40834). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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