rs11539507

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_030662.4(MAP2K2):c.660C>A(p.Ile220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,585,444 control chromosomes in the GnomAD database, including 177,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. I220I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.43 ( 14757 hom., cov: 31)

Exomes 𝑓: 0.47 ( 162519 hom. )

Consequence

MAP2K2
NM_030662.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -0.203

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 19-4101064-G-T is Benign according to our data. Variant chr19-4101064-G-T is described in ClinVar as [Benign]. Clinvar id is 40816.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-4101064-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.203 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAP2K2	NM_030662.4 linkuse as main transcript	c.660C>A	p.Ile220=	synonymous_variant	6/11	ENST00000262948.10
MAP2K2	XM_006722799.3 linkuse as main transcript	c.660C>A	p.Ile220=	synonymous_variant	6/9
MAP2K2	XM_047439100.1 linkuse as main transcript	c.90C>A	p.Ile30=	synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.660C>A	p.Ile220=	synonymous_variant	6/11	1	NM_030662.4	P1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65084

AN:

151796

Hom.:

14750

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.454

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.594

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.458

GnomAD3 exomes

AF:

0.478

AC:

98773

AN:

206634

Hom.:

24022

AF XY:

0.473

AC XY:

52611

AN XY:

111224

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.578

Gnomad ASJ exome

AF:

0.537

Gnomad EAS exome

AF:

0.593

Gnomad SAS exome

AF:

0.393

Gnomad FIN exome

AF:

0.457

Gnomad NFE exome

AF:

0.477

Gnomad OTH exome

AF:

0.491

GnomAD4 exome

AF:

0.474

AC:

678786

AN:

1433530

Hom.:

162519

Cov.:

AF XY:

0.472

AC XY:

335045

AN XY:

710580

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.571

Gnomad4 ASJ exome

AF:

0.537

Gnomad4 EAS exome

AF:

0.564

Gnomad4 SAS exome

AF:

0.398

Gnomad4 FIN exome

AF:

0.461

Gnomad4 NFE exome

AF:

0.478

Gnomad4 OTH exome

AF:

0.472

GnomAD4 genome

AF:

0.429

AC:

65113

AN:

151914

Hom.:

14757

Cov.:

AF XY:

0.428

AC XY:

31804

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.531

Gnomad4 ASJ

AF:

0.528

Gnomad4 EAS

AF:

0.594

Gnomad4 SAS

AF:

0.387

Gnomad4 FIN

AF:

0.461

Gnomad4 NFE

AF:

0.479

Gnomad4 OTH

AF:

0.457

Alfa

AF:

0.428

Hom.:

5775

Bravo

AF:

0.430

Asia WGS

AF:

0.469

AC:

1631

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Sep 21, 2007	- -

RASopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.660C>A (p.Ile220=) variant in the MAP2K2 gene is 65.271% (3631/5412) of Latino 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:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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

-0.39

Cadd

Benign

7.2

Dann

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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