chr15-66436912-C-T

Position:

chr15-66436912-C-T

Variant summary

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

The NM_002755.4(MAP2K1):c.438+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,613,606 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)

Exomes 𝑓: 0.025 ( 628 hom. )

Consequence

MAP2K1
NM_002755.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.191

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:

MAP2K1 (HGNC:):

MAP2K1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 15-66436912-C-T is Benign according to our data. Variant chr15-66436912-C-T is described in ClinVar as [Benign]. Clinvar id is 40749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-66436912-C-T is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
MAP2K1	NM_002755.4 linkuse as main transcript	c.438+20C>T	intron_variant	ENST00000307102.10	NP_002746.1	Q02750-1A4QPA9
MAP2K1	NM_001411065.1 linkuse as main transcript	c.372+20C>T	intron_variant		NP_001397994.1
MAP2K1	XM_011521783.4 linkuse as main transcript	c.372+20C>T	intron_variant		XP_011520085.1	B4DFY5
MAP2K1	XM_017022411.3 linkuse as main transcript	c.438+20C>T	intron_variant		XP_016877900.1	Q02750-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10 linkuse as main transcript	c.438+20C>T		intron_variant		1	NM_002755.4	ENSP00000302486.5		Q02750-1

Frequencies

GnomAD3 genomes

AF:

0.0174

AC:

2641

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.0540

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0211

GnomAD3 exomes

AF:

0.0251

AC:

6300

AN:

251342

Hom.:

113

AF XY:

0.0278

AC XY:

3778

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00344

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.0119

Gnomad SAS exome

AF:

0.0632

Gnomad FIN exome

AF:

0.0151

Gnomad NFE exome

AF:

0.0271

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0247

AC:

36107

AN:

1461314

Hom.:

628

Cov.:

AF XY:

0.0260

AC XY:

18903

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.00341

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.0209

Gnomad4 SAS exome

AF:

0.0643

Gnomad4 FIN exome

AF:

0.0149

Gnomad4 NFE exome

AF:

0.0237

Gnomad4 OTH exome

AF:

0.0232

GnomAD4 genome

AF:

0.0174

AC:

2646

AN:

152292

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1290

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00438

Gnomad4 AMR

AF:

0.0132

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.0158

Gnomad4 SAS

AF:

0.0551

Gnomad4 FIN

AF:

0.0129

Gnomad4 NFE

AF:

0.0246

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0163

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2019	Variant summary: MAP2K1 c.438+20C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.025 in 251342 control chromosomes in the gnomAD database, including 113 homozygotes. The observed variant frequency is approximately 10026 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.438+20C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

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

Cardiofaciocutaneous syndrome 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

RASopathy

Benign:1

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

-0.81

CADD

Benign

2.1

DANN

Benign

0.41

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