15-66387346-A-G

Position:

chr15-66387346-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002755.4(MAP2K1):c.-2A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,559,588 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 175 hom. )

Consequence

MAP2K1
NM_002755.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.394

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 15-66387346-A-G is Benign according to our data. Variant chr15-66387346-A-G is described in ClinVar as [Benign]. Clinvar id is 40738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66387346-A-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4 linkuse as main transcript	c.-2A>G		5_prime_UTR_variant	1/11	ENST00000307102.10	NP_002746.1
MAP2K1	XM_017022411.3 linkuse as main transcript	c.-2A>G		5_prime_UTR_variant	1/10		XP_016877900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10 linkuse as main transcript	c.-2A>G		5_prime_UTR_variant	1/11	1	NM_002755.4	ENSP00000302486	P1	Q02750-1

Frequencies

GnomAD3 genomes

AF:

0.00875

AC:

1331

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0318

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.0370

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00700

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.0171

AC:

2849

AN:

167082

Hom.:

AF XY:

0.0148

AC XY:

1311

AN XY:

88694

show subpopulations

Gnomad AFR exome

AF:

0.000906

Gnomad AMR exome

AF:

0.0680

Gnomad ASJ exome

AF:

0.00453

Gnomad EAS exome

AF:

0.0348

Gnomad SAS exome

AF:

0.00383

Gnomad FIN exome

AF:

0.00347

Gnomad NFE exome

AF:

0.00609

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.00866

AC:

12182

AN:

1407378

Hom.:

175

Cov.:

AF XY:

0.00853

AC XY:

5925

AN XY:

695002

show subpopulations

Gnomad4 AFR exome

AF:

0.00112

Gnomad4 AMR exome

AF:

0.0626

Gnomad4 ASJ exome

AF:

0.00385

Gnomad4 EAS exome

AF:

0.0562

Gnomad4 SAS exome

AF:

0.00405

Gnomad4 FIN exome

AF:

0.00363

Gnomad4 NFE exome

AF:

0.00625

Gnomad4 OTH exome

AF:

0.00705

GnomAD4 genome

AF:

0.00882

AC:

1342

AN:

152210

Hom.:

Cov.:

AF XY:

0.00869

AC XY:

647

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.0324

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.0371

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.00702

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00560

Hom.:

Bravo

AF:

0.0124

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2009	- -
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	Eurofins Ntd Llc (ga)	May 03, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 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 27, 2021

- -

RASopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.87

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

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