rs10424545

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.450+15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00827 in 1,612,562 control chromosomes in the GnomAD database, including 988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 518 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 470 hom. )

Consequence

MAP2K2
NM_030662.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.199

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=-0.86).

BP6

Variant 19-4110494-C-A is Benign according to our data. Variant chr19-4110494-C-A is described in ClinVar as [Benign]. Clinvar id is 40794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110494-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4 linkuse as main transcript	c.450+15G>T		intron_variant		ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.450+15G>T		intron_variant			XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.450+15G>T	intron_variant	1	NM_030662.4	ENSP00000262948	P1
MAP2K2	ENST00000394867.9 linkuse as main transcript	n.889+15G>T	intron_variant, non_coding_transcript_variant	5
MAP2K2	ENST00000599345.1 linkuse as main transcript	n.647+15G>T	intron_variant, non_coding_transcript_variant	5
MAP2K2	ENST00000687128.1 linkuse as main transcript	n.889+15G>T	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0437

AC:

6641

AN:

152134

Hom.:

515

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0118

AC:

2942

AN:

249874

Hom.:

212

AF XY:

0.00849

AC XY:

1148

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.00868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000697

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

AF:

0.00456

AC:

6664

AN:

1460310

Hom.:

470

Cov.:

AF XY:

0.00393

AC XY:

2858

AN XY:

726484

show subpopulations

Gnomad4 AFR exome

AF:

0.154

Gnomad4 AMR exome

AF:

0.00977

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.0438

AC:

6666

AN:

152252

Hom.:

518

Cov.:

AF XY:

0.0409

AC XY:

3043

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.152

Gnomad4 AMR

AF:

0.0150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.00660

Hom.:

Bravo

AF:

0.0498

Asia WGS

AF:

0.0110

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:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2012	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: MAP2K2 c.450+15G>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. Several computational tools predict a significant impact on normal splicing: Three predict that the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 249874 control chromosomes, predominantly at a frequency of 0.16 within the African or African-American subpopulation in the gnomAD database, including 209 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 64000-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 a benign polymorphism found primarily in populations of African or African-American origin. 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.1

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

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