rs8157

chr19-4117530-G-Achr19-4117530-G-Cchr19-4117530-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_030662.4(MAP2K2):c.192C>T(p.Val64=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,614,010 control chromosomes in the GnomAD database, including 3,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.064 (326 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3047 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -2.81

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-4117530-G-A is Benign according to our data. Variant chr19-4117530-G-A is described in ClinVar as [Benign]. Clinvar id is 40770.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-4117530-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.192C>T	p.Val64=	synonymous_variant	2/11	ENST00000262948.10
MAP2K2	XM_006722799.3	c.192C>T	p.Val64=	synonymous_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.192C>T	p.Val64=	synonymous_variant	2/11	1	NM_030662.4	P1
MAP2K2	ENST00000394867.9	n.631C>T		non_coding_transcript_exon_variant	1/10	5
MAP2K2	ENST00000599345.1	n.389C>T		non_coding_transcript_exon_variant	2/7	5
MAP2K2	ENST00000687128.1	n.631C>T		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9714 AN: 152126 Hom.: 326 Cov.: 33

Gnomad AFR AF: 0.0769

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0192

Gnomad SAS AF: 0.0693

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.0602

GnomAD3 exomes AF: 0.0595 AC: 14949 AN: 251330 Hom.: 527 AF XY: 0.0619 AC XY: 8417 AN XY: 135896

Gnomad AFR exome AF: 0.0761

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0560

Gnomad EAS exome AF: 0.0242

Gnomad SAS exome AF: 0.0784

Gnomad FIN exome AF: 0.0769

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0624 AC: 91175 AN: 1461766 Hom.: 3047 Cov.: 37 AF XY: 0.0630 AC XY: 45842 AN XY: 727188

Gnomad4 AFR exome AF: 0.0760

Gnomad4 AMR exome AF: 0.0304

Gnomad4 ASJ exome AF: 0.0537

Gnomad4 EAS exome AF: 0.0142

Gnomad4 SAS exome AF: 0.0781

Gnomad4 FIN exome AF: 0.0784

Gnomad4 NFE exome AF: 0.0634

Gnomad4 OTH exome AF: 0.0594

GnomAD4 genome AF: 0.0638 AC: 9718 AN: 152244 Hom.: 326 Cov.: 33 AF XY: 0.0627 AC XY: 4664 AN XY: 74432

Gnomad4 AFR AF: 0.0768

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0697

Gnomad4 FIN AF: 0.0711

Gnomad4 NFE AF: 0.0646

Gnomad4 OTH AF: 0.0595

Alfa AF: 0.0634 Hom.: 128

Bravo AF: 0.0614

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.0667

EpiControl AF: 0.0587

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2015	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 18, 2008	- -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.192C>T (p.Val64=) variant in the MAP2K2 gene is 7.417% (1283/16512) of South Asian 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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 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. -

Cardiofaciocutaneous syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	6.2
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8157; hg19: chr19-4117528; COSMIC: COSV53562298;