rs17851657

Variant names:

• chr19-4102451-G-A
• rs17851657
• NM_030662.4:c.453C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-4102451-G-A
• chr19-4102451-G-C
• chr19-4102451-G-T

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
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: -0.278

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]

ACMG classification

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 rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.453C>T	p.Asp151Asp	splice_region_variant, synonymous_variant	Exon 4 of 11	ENST00000262948.10	NP_109587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.453C>T	p.Asp151Asp	splice_region_variant, synonymous_variant	Exon 4 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21512 AN: 152112 Hom.: 1967 Cov.: 33

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

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.: 31 AF XY: 0.189 AC XY: 135803 AN XY: 716686

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.: 33 AF XY: 0.140 AC XY: 10386 AN XY: 74422

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:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Jan 24, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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) -

-

Baylor Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Cardiofaciocutaneous syndrome 4 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Jan 21, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs17851657; hg19: chr19-4102449; COSMIC: COSV53562460; COSMIC: COSV53562460;