15-66484977-GTC-GTCTC

Position:

chr15-66484977-GTC-GTCTC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP5BP7

This summary comes from the ClinGen Evidence Repository: The c.694-8_694-7dupTC variant is an intronic variant located in intron 6 of the MAP2K1 gene. The filtering allele frequency in gnomAD v4.1.0 is 4.669% (3488/74934 alleles) in the African/African American population, which meets the threshold to apply BA1. The computational predictor SpliceAI predicts no impact on splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL genetics internal data 26957, 21766, 500060; ClinVar SCV000111925.5; SCV000204171.4; SCV000207934.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5, BP7 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA147595/MONDO:0021060/045

Frequency

Genomes: 𝑓 0.013 ( 37 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 44 hom. )

Consequence

MAP2K1
NM_002755.4 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: 1.47

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP5

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

BP7

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
MAP2K1	NM_002755.4 linkuse as main transcript	c.694-8_694-7dup	splice_polypyrimidine_tract_variant, intron_variant	ENST00000307102.10	NP_002746.1
MAP2K1	NM_001411065.1 linkuse as main transcript	c.550-8_550-7dup	splice_polypyrimidine_tract_variant, intron_variant		NP_001397994.1
MAP2K1	XM_011521783.4 linkuse as main transcript	c.628-8_628-7dup	splice_polypyrimidine_tract_variant, intron_variant		XP_011520085.1
MAP2K1	XM_017022411.3 linkuse as main transcript	c.616-8_616-7dup	splice_polypyrimidine_tract_variant, intron_variant		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10 linkuse as main transcript	c.694-8_694-7dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002755.4	ENSP00000302486	P1	Q02750-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1975

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00370

AC:

930

AN:

251352

Hom.:

AF XY:

0.00272

AC XY:

370

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0492

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00142

AC:

2064

AN:

1458588

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

849

AN XY:

725780

show subpopulations

Gnomad4 AFR exome

AF:

0.0487

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000919

Gnomad4 OTH exome

AF:

0.00331

GnomAD4 genome

AF:

0.0130

AC:

1977

AN:

152302

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

921

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0449

Gnomad4 AMR

AF:

0.00490

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00514

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.00231

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2011	694-8_694-7dupTC in intron 6 of MEK1: This variant (rs 113913469, no frequency i nformation) is not expected to have clinical significance because it has been id entified in as many as 0.94% (12/1275) probands including 11.8% (8/68) Black pro bands in our laboratory and is not located in the highly conserved region of the splicing consensus sequence. In addition, it has been identified in four other individuals with clinical features of Noonan spectrum disorders and another path ogenic variant tested by our laboratory. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2023	- -

RASopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.694-8_694-7dupTC variant is an intronic variant located in intron 6 of the MAP2K1 gene. The filtering allele frequency in gnomAD v4.1.0 is 4.669% (3488/74934 alleles) in the African/African American population, which meets the threshold to apply BA1. The computational predictor SpliceAI predicts no impact on splicing (BP7). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL genetics internal data 26957, 21766, 500060; ClinVar SCV000111925.5; SCV000204171.4; SCV000207934.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP5, BP7 (Specification Version 2.1, 09/17/2024) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cardio-facio-cutaneous syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Noonan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over