15-66485007-G-A

Variant names:

• chr15-66485007-G-A
• rs17586159
• NM_002755.4:c.711G>A

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.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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134613/MONDO:0021060/004

• 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:12
• Conservation: PhyloP100: -0.509
• Publications: 15 publications found

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: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	NM_002755.4	MANE Select	c.711G>A	p.Gly237Gly	synonymous	Exon 7 of 11	NP_002746.1	Q02750-1
	MAP2K1	NM_001411065.1		c.567G>A	p.Gly189Gly	synonymous	Exon 6 of 10	NP_001397994.1	A0A8I5KYS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K1	ENST00000307102.10	TSL:1 MANE Select	c.711G>A	p.Gly237Gly	synonymous	Exon 7 of 11	ENSP00000302486.5	Q02750-1
	MAP2K1	ENST00000685172.1		c.711G>A	p.Gly237Gly	synonymous	Exon 7 of 10	ENSP00000509604.1	A0A8I5KYB4
	MAP2K1	ENST00000689951.1		c.762G>A	p.Gly254Gly	synonymous	Exon 8 of 12	ENSP00000509308.1	A0A8I5KRX5

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

GnomAD2 exomes AF: 0.0117 AC: 2931 AN: 251444 AF XY: 0.0116

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 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

African (AFR) AF: 0.00206 AC: 69 AN: 33444

American (AMR) AF: 0.00772 AC: 345 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 457 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00554 AC: 478 AN: 86220

European-Finnish (FIN) AF: 0.00648 AC: 346 AN: 53408

Middle Eastern (MID) AF: 0.00464 AC: 24 AN: 5172

European-Non Finnish (NFE) AF: 0.0206 AC: 22921 AN: 1111948

Other (OTH) AF: 0.0134 AC: 811 AN: 60312

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

African (AFR) AF: 0.00392 AC: 163 AN: 41570

American (AMR) AF: 0.0102 AC: 156 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4822

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1349 AN: 68024

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0166 Hom.: 34

Bravo AF: 0.0119

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0162

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.7
DANN	Benign	0.70
PhyloP100		-0.51
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs17586159; hg19: chr15-66777345; COSMIC: COSV61070996;