rs41306345

Positions:

• chr15-66489710-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1023-8C>T variant in the MAP2K1 gene is 10.315% (1128/10406) of African 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/CA134590/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.093 (645 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5373 hom.)
• Consequence: MAP2K1 NM_002755.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003322
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.321

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.1023-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000307102.10	NP_002746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.1023-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002755.4	ENSP00000302486	P1
	ENST00000565387.2	n.1116G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14067 AN: 152068 Hom.: 643 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0719

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.0817

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.0856

GnomAD3 exomes AF: 0.0840 AC: 21132 AN: 251480 Hom.: 916 AF XY: 0.0845 AC XY: 11485 AN XY: 135914

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0568

Gnomad ASJ exome AF: 0.0860

Gnomad EAS exome AF: 0.0480

Gnomad SAS exome AF: 0.0844

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.0894

GnomAD4 exome AF: 0.0842 AC: 122769 AN: 1458072 Hom.: 5373 Cov.: 30 AF XY: 0.0842 AC XY: 61084 AN XY: 725642

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0585

Gnomad4 ASJ exome AF: 0.0896

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0843

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0841

Gnomad4 OTH exome AF: 0.0869

GnomAD4 genome AF: 0.0925 AC: 14084 AN: 152188 Hom.: 645 Cov.: 32 AF XY: 0.0932 AC XY: 6932 AN XY: 74406

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0719

Gnomad4 ASJ AF: 0.0953

Gnomad4 EAS AF: 0.0417

Gnomad4 SAS AF: 0.0807

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.0865

Gnomad4 OTH AF: 0.0848

Alfa AF: 0.0870 Hom.: 390

Bravo AF: 0.0903

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.0887

EpiControl AF: 0.0890

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

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	Oct 03, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

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	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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.1023-8C>T variant in the MAP2K1 gene is 10.315% (1128/10406) of African 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.0080
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: rs41306345; hg19: chr15-66782048; COSMIC: COSV57233926; COSMIC: COSV57233926;