rs545661620

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_002755.4(MAP2K1):c.1068+12_1068+15del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,610,934 control chromosomes in the GnomAD database, including 9 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 7 hom. )

Consequence

MAP2K1
NM_002755.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:2B:12

Conservation

PhyloP100: -0.0830

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 15-66489770-CTATT-C is Benign according to our data. Variant chr15-66489770-CTATT-C is described in ClinVar as [Benign]. Clinvar id is 44586.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-66489770-CTATT-C is described in Lovd as [Likely_benign]. Variant chr15-66489770-CTATT-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00223 (340/152328) while in subpopulation NFE AF= 0.00338 (230/68020). AF 95% confidence interval is 0.00302. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K1	NM_002755.4 linkuse as main transcript	c.1068+12_1068+15del		splice_region_variant, intron_variant		ENST00000307102.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K1	ENST00000307102.10 linkuse as main transcript	c.1068+12_1068+15del		splice_region_variant, intron_variant		1	NM_002755.4	P1	Q02750-1
	ENST00000565387.2 linkuse as main transcript	n.1052_1055del		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

340

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00223

AC:

560

AN:

251462

Hom.:

AF XY:

0.00223

AC XY:

303

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00304

AC:

4427

AN:

1458606

Hom.:

AF XY:

0.00298

AC XY:

2162

AN XY:

725872

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00655

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000318

Gnomad4 NFE exome

AF:

0.00358

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.00223

AC:

340

AN:

152328

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00338

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00327

Hom.:

Bravo

AF:

0.00248

EpiCase

AF:

0.00469

EpiControl

AF:

0.00456

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2019	Variant summary: MAP2K1 c.1068+12_1068+15delTATT 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. 5/5 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 0.0022 in 251462 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1440 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1068+12_1068+15delTATT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions including an expert panel, ClinGen, (evaluation after 2014) cite the variant three times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2015	c.1068+12_1068+15delTATT in intron 10 of MAP2K1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0 .3% (214/66740) of European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org). -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ENSG00000261351: BS2; MAP2K1: BS2 -

RASopathy

Benign:3

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.1068+12_1068+15delTATT variant in the MAP2K1 gene is 0.285% (214/66740) 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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2012	The variant is found in NOONAN panel(s). -

Noonan syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cardio-facio-cutaneous syndrome

Uncertain:1

Uncertain significance, 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 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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