rs350911

Positions:

Variant summary

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

The NM_030662.4(MAP2K2):c.919+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,590,206 control chromosomes in the GnomAD database, including 427,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 42595 hom., cov: 33)

Exomes 𝑓: 0.73 ( 384418 hom. )

Consequence

MAP2K2
NM_030662.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.898

Variant links:

Genes affected

MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

MAP2K2 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=-0.88).

BP6

Variant 19-4099189-T-C is Benign according to our data. Variant chr19-4099189-T-C is described in ClinVar as [Benign]. Clinvar id is 40835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4099189-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
MAP2K2	NM_030662.4 linkuse as main transcript	c.919+12A>G	intron_variant	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.705+1830A>G	intron_variant		XP_006722862.1
MAP2K2	XM_047439100.1 linkuse as main transcript	c.349+12A>G	intron_variant		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.919+12A>G		intron_variant		1	NM_030662.4	ENSP00000262948	P1

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113609

AN:

152032

Hom.:

42566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.744

Gnomad AMI

AF:

0.714

Gnomad AMR

AF:

0.803

Gnomad ASJ

AF:

0.703

Gnomad EAS

AF:

0.934

Gnomad SAS

AF:

0.713

Gnomad FIN

AF:

0.769

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.725

Gnomad OTH

AF:

0.728

GnomAD3 exomes

AF:

0.753

AC:

157211

AN:

208772

Hom.:

59727

AF XY:

0.747

AC XY:

85711

AN XY:

114752

show subpopulations

Gnomad AFR exome

AF:

0.738

Gnomad AMR exome

AF:

0.849

Gnomad ASJ exome

AF:

0.714

Gnomad EAS exome

AF:

0.921

Gnomad SAS exome

AF:

0.706

Gnomad FIN exome

AF:

0.752

Gnomad NFE exome

AF:

0.713

Gnomad OTH exome

AF:

0.728

GnomAD4 exome

AF:

0.730

AC:

1049346

AN:

1438056

Hom.:

384418

Cov.:

AF XY:

0.729

AC XY:

520249

AN XY:

713878

show subpopulations

Gnomad4 AFR exome

AF:

0.730

Gnomad4 AMR exome

AF:

0.841

Gnomad4 ASJ exome

AF:

0.717

Gnomad4 EAS exome

AF:

0.935

Gnomad4 SAS exome

AF:

0.713

Gnomad4 FIN exome

AF:

0.754

Gnomad4 NFE exome

AF:

0.719

Gnomad4 OTH exome

AF:

0.733

GnomAD4 genome

AF:

0.747

AC:

113687

AN:

152150

Hom.:

42595

Cov.:

AF XY:

0.750

AC XY:

55763

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.744

Gnomad4 AMR

AF:

0.803

Gnomad4 ASJ

AF:

0.703

Gnomad4 EAS

AF:

0.934

Gnomad4 SAS

AF:

0.712

Gnomad4 FIN

AF:

0.769

Gnomad4 NFE

AF:

0.725

Gnomad4 OTH

AF:

0.727

Alfa

AF:

0.730

Hom.:

8639

Bravo

AF:

0.750

Asia WGS

AF:

0.809

AC:

2811

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	Variant summary: MAP2K2 c.919+12A>G 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 0.75 in 208772 control chromosomes, suggesting that it is the major allele and therefore benign. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiofaciocutaneous syndrome 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

-0.88

CADD

Benign

1.7

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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