rs727504317

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2PP3PM2PS3PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.199G>A (p.Asp67Asn) variant in MAP2K1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17704260). In vitro functional studies provide some evidence that the p.Asp67Asn variant may impact protein function (PS3; PMID 25049390). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Asp67Asn variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180743/MONDO:0015280/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAP2K1
NM_002755.4 missense

Scores

8

8

2

Clinical Significance

Pathogenic reviewed by expert panel P:18O:2

Conservation

PhyloP100: 9.86

Publications

87 publications found

Variant links:

Genes affected

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

MAP2K1 Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
cardiofaciocutaneous syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
Noonan syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MAP2K1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

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

PM2

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

PM6

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

PP2

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

PP3

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.199G>A	p.Asp67Asn	missense	Exon 2 of 11	NP_002746.1
	MAP2K1	NM_001411065.1		c.133G>A	p.Asp45Asn	missense	Exon 2 of 10	NP_001397994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.199G>A	p.Asp67Asn	missense	Exon 2 of 11	ENSP00000302486.5
	MAP2K1	ENST00000685172.1		c.199G>A	p.Asp67Asn	missense	Exon 2 of 10	ENSP00000509604.1
	MAP2K1	ENST00000689951.1		c.199G>A	p.Asp67Asn	missense	Exon 2 of 12	ENSP00000509308.1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

0

AN:

1461864

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

727234

African (AFR)

AF:

0.00

AC:

0

AN:

33478

American (AMR)

AF:

0.00

AC:

0

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

1111998

Other (OTH)

AF:

0.00

AC:

0

AN:

60396

GnomAD4 genome

Cov.:

32

Alfa

AF:

0.00

Hom.:

0

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

7

-

-

Cardiofaciocutaneous syndrome 3 (8)

2

-

-

Cardiofaciocutaneous syndrome 1 (2)

2

-

-

not provided (2)

1

-

-

Autism spectrum disorder (1)

1

-

-

Cardio-facio-cutaneous syndrome (2)

1

-

-

Cardiovascular phenotype (1)

1

-

-

MAP2K1-related RASopathy (1)

1

-

-

Melorheostosis;C3809006:Cardiofaciocutaneous syndrome 3 (1)

1

-

-

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome (1)

1

-

-

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.089

D

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

33

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.89

D

M_CAP

Pathogenic

0.30

D

MetaRNN

Pathogenic

0.93

D

MetaSVM

Benign

-0.30

T

MutationAssessor

Uncertain

2.7

M

PhyloP100

9.9

PrimateAI

Pathogenic

0.90

D

PROVEAN

Uncertain

-3.3

D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.021

D

Sift4G

Uncertain

0.029

D

Polyphen

0.99

D

Vest4

0.76

MutPred

0.78

Gain of methylation at K64 (P = 0.0585)

MVP

0.90

MPC

1.3

ClinPred

0.98

D

GERP RS

5.2

Varity_R

0.76

gMVP

0.89

Mutation Taster

=9/91

disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs727504317; hg19: chr15-66727483; COSMIC: COSV61068427; API