rs17586159

chr15-66485007-G-Achr15-66485007-G-Cchr15-66485007-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002755.4(MAP2K1):c.711G>A(p.Gly237=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,370 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 32)
  • Exomes 𝑓: 0.017 (257 hom.)
• Consequence: MAP2K1 NM_002755.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: -0.509

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 15-66485007-G-A is Benign according to our data. Variant chr15-66485007-G-A is described in ClinVar as [Benign]. Clinvar id is 40754.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-66485007-G-A is described in Lovd as [Benign]. Variant chr15-66485007-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.509 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1821/152314) while in subpopulation NFE AF= 0.0198 (1349/68024). AF 95% confidence interval is 0.019. There are 17 homozygotes in gnomad4. There are 826 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1822 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4	c.711G>A	p.Gly237=	synonymous_variant	7/11	ENST00000307102.10
MAP2K1	NM_001411065.1	c.567G>A	p.Gly189=	synonymous_variant	6/10
MAP2K1	XM_011521783.4	c.645G>A	p.Gly215=	synonymous_variant	7/11
MAP2K1	XM_017022411.3	c.633G>A	p.Gly211=	synonymous_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10	c.711G>A	p.Gly237=	synonymous_variant	7/11	1	NM_002755.4	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1822 AN: 152196 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.0117 AC: 2931 AN: 251444 Hom.: 17 AF XY: 0.0116 AC XY: 1574 AN XY: 135890

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00769

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0174 AC: 25453 AN: 1461056 Hom.: 257 Cov.: 32 AF XY: 0.0170 AC XY: 12375 AN XY: 726826

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00772

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00554

Gnomad4 FIN exome AF: 0.00648

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0120 AC: 1821 AN: 152314 Hom.: 17 Cov.: 32 AF XY: 0.0111 AC XY: 826 AN XY: 74478

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0173 Hom.: 34

Bravo AF: 0.0119

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2007	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -

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.711G>A (p.Gly237=) variant in the MAP2K1 gene is 1.612% (1130/66724) of European 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	Jan 31, 2024	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 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. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.7
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17586159; hg19: chr15-66777345; COSMIC: COSV61070996; COSMIC: COSV61070996;