chr15-66387416-C-T

Variant names:

• chr15-66387416-C-T
• rs140749690
• NM_002755.4:c.69C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.69C>T (p.Thr23=) variant in the MAP2K1 gene is 0.0484% (4/2820) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA181309/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: MAP2K1 NM_002755.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:8
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.69C>T	p.Thr23Thr	synonymous_variant	Exon 1 of 11	ENST00000307102.10	NP_002746.1
MAP2K1	XM_017022411.3	c.69C>T	p.Thr23Thr	synonymous_variant	Exon 1 of 10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.69C>T	p.Thr23Thr	synonymous_variant	Exon 1 of 11	1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000792 AC: 13 AN: 164198 Hom.: 0 AF XY: 0.0000690 AC XY: 6 AN XY: 86978

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.0000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.0000455 AC: 64 AN: 1406886 Hom.: 0 Cov.: 32 AF XY: 0.0000389 AC XY: 27 AN XY: 694648

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.0000547

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000554

Gnomad4 OTH exome AF: 0.000223

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74460

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000574

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Oct 04, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MAP2K1 c.69C>T (p.Thr23Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. MutationTaster predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may introduce an SF2/ASF ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 25/188032 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001386 (24/17310). This frequency is about 554 times the estimated maximal expected allele frequency of a pathogenic MAP2K1 variant (0.0000025), strongly suggesting this is likely a benign polymorphism found primarily in populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign or benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Dec 05, 2013

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. -

Feb 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr23Thr in exon 1 of MAP2K1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (4/2820) of A frican chromosomes by the Exome Aggregation Consortium Project (ExAC, http://exa c.broadinstitute.org/; dbSNP rs140749690). -

RASopathy Benign:2

May 09, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.69C>T (p.Thr23=) variant in the MAP2K1 gene is 0.0484% (4/2820) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MAP2K1-related disorder Benign:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Apr 19, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.43
CADD	Benign	14
DANN	Benign	0.97

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: rs140749690; hg19: chr15-66679754;