rs116988721

Positions:

chr19-4117401-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030662.4(MAP2K2):c.303+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,610,442 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 10 hom., cov: 33)

Exomes 𝑓: 0.012 ( 126 hom. )

Consequence

MAP2K2
NM_030662.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.434

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:

MAP2K2 (HGNC:):

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=-0.95).

BP6

Variant 19-4117401-C-T is Benign according to our data. Variant chr19-4117401-C-T is described in ClinVar as [Benign]. Clinvar id is 40789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4117401-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00872 (1328/152336) while in subpopulation NFE AF= 0.0136 (927/68030). AF 95% confidence interval is 0.0129. There are 10 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4 linkuse as main transcript	c.303+18G>A		intron_variant		ENST00000262948.10	NP_109587.1	P36507
MAP2K2	XM_006722799.3 linkuse as main transcript	c.303+18G>A		intron_variant			XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.303+18G>A	intron_variant	1	NM_030662.4	ENSP00000262948.4	P36507
MAP2K2	ENST00000394867.9 linkuse as main transcript	n.742+18G>A	intron_variant	5
MAP2K2	ENST00000599345.1 linkuse as main transcript	n.500+18G>A	intron_variant	5
MAP2K2	ENST00000687128.1 linkuse as main transcript	n.742+18G>A	intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00872

AC:

1327

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00890

AC:

2205

AN:

247876

Hom.:

AF XY:

0.00902

AC XY:

1215

AN XY:

134658

show subpopulations

Gnomad AFR exome

AF:

0.00278

Gnomad AMR exome

AF:

0.00746

Gnomad ASJ exome

AF:

0.00652

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00239

Gnomad FIN exome

AF:

0.00960

Gnomad NFE exome

AF:

0.0132

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0121

AC:

17584

AN:

1458106

Hom.:

126

Cov.:

AF XY:

0.0120

AC XY:

8693

AN XY:

725420

show subpopulations

Gnomad4 AFR exome

AF:

0.00240

Gnomad4 AMR exome

AF:

0.00710

Gnomad4 ASJ exome

AF:

0.00640

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00291

Gnomad4 FIN exome

AF:

0.00967

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00872

AC:

1328

AN:

152336

Hom.:

Cov.:

AF XY:

0.00839

AC XY:

625

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.00778

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0108

Gnomad4 NFE

AF:

0.0136

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00817

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: MAP2K2 c.303+18G>A 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site. One predicts the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0089 in 247876 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 3558-folds over the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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

- -

Cardiofaciocutaneous syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.22

DANN

Benign

0.62

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