chr19-4099336-C-T

Position:

chr19-4099336-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.784G>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 262 (p.Val262Ile). The filtering allele frequency in gnomAD v4.1.0 is 0.01543% (201/1178752 alleles) in the European (non-Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.219, which predicts no impact on protein function (BP4). This variant has been identified in 4 independent occurrences in patients with disparate phenotypes of RASopathy (PS4 not met; GeneDx, LMM internal data; GTR ID's 26957, 21766; SCV000207950.9, SCV000063182.5). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137966/MONDO:0021060/048

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:3

Conservation

PhyloP100: 2.85

Variant links:

Genes affected

MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

MAP2K2 links:

MAP2K2 (HGNC:):

MAP2K2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4 linkuse as main transcript	c.784G>A	p.Val262Ile	missense_variant	7/11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	XM_047439100.1 linkuse as main transcript	c.214G>A	p.Val72Ile	missense_variant	5/9		XP_047295056.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.705+1683G>A		intron_variant			XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.784G>A	p.Val262Ile	missense_variant	7/11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000576

AC:

AN:

243172

Hom.:

AF XY:

0.0000529

AC XY:

AN XY:

132260

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.0000998

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1458164

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

725210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000902

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000583

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000151

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2020	Variant summary: MAP2K2 c.784G>A (p.Val262Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 243172 control chromosomes (gnomAD). The observed variant frequency is approximately 23-fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.784G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Evidence provided in ClinVar database report 4 independent occurrences of the variant in patients with a RASopathy (ClinVar SCV000616544.3). However, the submitters that provided these internal data both cite the variant as likely benign (evaluation before 2014) (ClinVar SCV000207950.9, SCV000063182.5). A publication, Brnich et al (2018), utilizing an algorithmic analysis of the ACMG/AMP rules assessed the variant to be likely benign. Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2010	- -

RASopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 262 of the MAP2K2 protein (p.Val262Ile). This variant is present in population databases (rs138873805, gnomAD 0.01%). 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: 46242). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt MAP2K2 function with a negative predictive value of 95%. 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.784G>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 262 (p.Val262Ile). The filtering allele frequency in gnomAD v4.1.0 is 0.01543% (201/1178752 alleles) in the European (non-Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.219, which predicts no impact on protein function (BP4). This variant has been identified in 4 independent occurrences in patients with disparate phenotypes of RASopathy (PS4 not met; GeneDx, LMM internal data; GTR ID's 26957, 21766; SCV000207950.9, SCV000063182.5). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 9/17/2024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.097

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.39

N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

0.50

N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.23

MVP

0.26

MPC

0.36

ClinPred

0.013

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over