rs17851657

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137943/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.14 ( 1972 hom., cov: 33)

Exomes 𝑓: 0.19 ( 27044 hom. )

Consequence

MAP2K2
NM_030662.4 splice_region, synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: -0.278

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAP2K2	NM_030662.4 linkuse as main transcript	c.453C>T	p.Asp151=	splice_region_variant, synonymous_variant	4/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.453C>T	p.Asp151=	splice_region_variant, synonymous_variant	4/9		XP_006722862.1
MAP2K2	XM_047439100.1 linkuse as main transcript	c.-118C>T		splice_region_variant, 5_prime_UTR_variant	2/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.453C>T	p.Asp151=	splice_region_variant, synonymous_variant	4/11	1	NM_030662.4	ENSP00000262948	P1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21512

AN:

152112

Hom.:

1967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0441

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.0430

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.154

GnomAD3 exomes

AF:

0.163

AC:

36340

AN:

222968

Hom.:

3477

AF XY:

0.170

AC XY:

20555

AN XY:

120626

show subpopulations

Gnomad AFR exome

AF:

0.0416

Gnomad AMR exome

AF:

0.0893

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.0350

Gnomad SAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.188

AC:

271555

AN:

1443232

Hom.:

27044

Cov.:

AF XY:

0.189

AC XY:

135803

AN XY:

716686

show subpopulations

Gnomad4 AFR exome

AF:

0.0397

Gnomad4 AMR exome

AF:

0.0933

Gnomad4 ASJ exome

AF:

0.220

Gnomad4 EAS exome

AF:

0.0531

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.186

Gnomad4 NFE exome

AF:

0.200

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

AF:

0.141

AC:

21533

AN:

152230

Hom.:

1972

Cov.:

AF XY:

0.140

AC XY:

10386

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0441

Gnomad4 AMR

AF:

0.128

Gnomad4 ASJ

AF:

0.230

Gnomad4 EAS

AF:

0.0431

Gnomad4 SAS

AF:

0.202

Gnomad4 FIN

AF:

0.176

Gnomad4 NFE

AF:

0.196

Gnomad4 OTH

AF:

0.160

Alfa

AF:

0.178

Hom.:

1281

Bravo

AF:

0.132

Asia WGS

AF:

0.143

AC:

501

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 29, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

RASopathy

Benign:3

Benign, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.453C>T (p.Asp151=) variant in the MAP2K2 gene is 27.128% (10569/38338) of European 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) -

Cardiofaciocutaneous syndrome 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.24

DANN

Benign

0.77

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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