rs73918030

Variant summary

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

The NM_030662.4(MAP2K2):c.528+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,578,872 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 401 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 335 hom. )

Consequence

MAP2K2
NM_030662.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.21

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=-0.82).

BP6

Variant 19-4102356-T-C is Benign according to our data. Variant chr19-4102356-T-C is described in ClinVar as [Benign]. Clinvar id is 40804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4102356-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
MAP2K2	NM_030662.4 linkuse as main transcript	c.528+20A>G	intron_variant	ENST00000262948.10
MAP2K2	XM_006722799.3 linkuse as main transcript	c.528+20A>G	intron_variant
MAP2K2	XM_047439100.1 linkuse as main transcript	c.-43+20A>G	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.528+20A>G		intron_variant		1	NM_030662.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5891

AN:

151742

Hom.:

402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000737

Gnomad OTH

AF:

0.0259

GnomAD3 exomes

AF:

0.00949

AC:

1922

AN:

202448

Hom.:

113

AF XY:

0.00671

AC XY:

732

AN XY:

109088

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.00653

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000115

Gnomad FIN exome

AF:

0.0000657

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.00381

GnomAD4 exome

AF:

0.00400

AC:

5709

AN:

1427012

Hom.:

335

Cov.:

AF XY:

0.00337

AC XY:

2382

AN XY:

707532

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.00681

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000110

Gnomad4 FIN exome

AF:

0.0000210

Gnomad4 NFE exome

AF:

0.000378

Gnomad4 OTH exome

AF:

0.00892

GnomAD4 genome

AF:

0.0388

AC:

5893

AN:

151860

Hom.:

401

Cov.:

AF XY:

0.0376

AC XY:

2791

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.0136

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000737

Gnomad4 OTH

AF:

0.0256

Alfa

AF:

0.0225

Hom.:

Bravo

AF:

0.0439

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2019	Variant summary: MAP2K2 c.528+20A>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 0.0095 in 202448 control chromosomes, predominantly at a frequency of 0.14 within the African or African-American subpopulation in the gnomAD database, including 113 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 56000-fold of 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. To our knowledge, no occurrence of c.528+20A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation submitted in 2016) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

RASopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

Cadd

Benign

0.98

Dann

Benign

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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