rs8157

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137916/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.064 ( 326 hom., cov: 33)

Exomes 𝑓: 0.062 ( 3047 hom. )

Consequence

MAP2K2
NM_030662.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: -2.81

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
cardiofaciocutaneous syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Noonan syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MAP2K2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 link	c.192C>T	p.Val64Val	synonymous_variant	Exon 2 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1 link	c.192C>T	p.Val64Val	synonymous_variant	Exon 2 of 9		NP_001427617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MAP2K2	ENST00000262948.10 link	c.192C>T	p.Val64Val	synonymous_variant	Exon 2 of 11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9 link	n.631C>T		non_coding_transcript_exon_variant	Exon 1 of 10	5
MAP2K2	ENST00000599345.1 link	n.389C>T		non_coding_transcript_exon_variant	Exon 2 of 7	5
MAP2K2	ENST00000687128.1 link	n.631C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Frequencies

GnomAD3 genomes

AF:

0.0639

AC:

9714

AN:

152126

Hom.:

326

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0595

AC:

14949

AN:

251330

AF XY:

0.0619

show subpopulations

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 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.:

AF XY:

0.0630

AC XY:

45842

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0760

AC:

2546

AN:

33480

American (AMR)

AF:

0.0304

AC:

1359

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0537

AC:

1403

AN:

26136

East Asian (EAS)

AF:

0.0142

AC:

564

AN:

39696

South Asian (SAS)

AF:

0.0781

AC:

6733

AN:

86258

European-Finnish (FIN)

AF:

0.0784

AC:

4180

AN:

53328

Middle Eastern (MID)

AF:

0.0543

AC:

313

AN:

5768

European-Non Finnish (NFE)

AF:

0.0634

AC:

70490

AN:

1111984

Other (OTH)

AF:

0.0594

AC:

3587

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5869

11738

17608

23477

29346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2566

5132

7698

10264

12830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0638

AC:

9718

AN:

152244

Hom.:

326

Cov.:

AF XY:

0.0627

AC XY:

4664

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0768

AC:

3188

AN:

41528

American (AMR)

AF:

0.0405

AC:

619

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

171

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5188

South Asian (SAS)

AF:

0.0697

AC:

337

AN:

4832

European-Finnish (FIN)

AF:

0.0711

AC:

754

AN:

10602

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0646

AC:

4390

AN:

68006

Other (OTH)

AF:

0.0595

AC:

126

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

499

997

1496

1994

2493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0633

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:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 18, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2015

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. -

RASopathy

Benign:2

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.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) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Apr 17, 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. -

Cardiofaciocutaneous syndrome 4

Benign:1

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.2

(source)

DANN

Benign

0.80

PhyloP100

-2.8

Mutation Taster

=293/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over