rs144850779

chr19-4090607-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_030662.4(MAP2K2):c.1194C>T(p.Thr398=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,550,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -2.60

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-4090607-G-A is Benign according to our data. Variant chr19-4090607-G-A is described in ClinVar as [Benign]. Clinvar id is 40846.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-2.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000188 (263/1398640) while in subpopulation AMR AF= 0.000503 (18/35792). AF 95% confidence interval is 0.000325. There are 1 homozygotes in gnomad4_exome. There are 133 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.1194C>T	p.Thr398=	synonymous_variant	11/11	ENST00000262948.10
MAP2K2	XM_006722799.3	c.915C>T	p.Thr305=	synonymous_variant	9/9
MAP2K2	XM_047439100.1	c.624C>T	p.Thr208=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.1194C>T	p.Thr398=	synonymous_variant	11/11	1	NM_030662.4	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000510 AC: 80 AN: 156826 Hom.: 0 AF XY: 0.000482 AC XY: 40 AN XY: 82976

Gnomad AFR exome AF: 0.000114

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00669

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000903

GnomAD4 exome AF: 0.000188 AC: 263 AN: 1398640 Hom.: 1 Cov.: 31 AF XY: 0.000193 AC XY: 133 AN XY: 690066

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000503

Gnomad4 ASJ exome AF: 0.00663

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000445

Gnomad4 OTH exome AF: 0.000500

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74374

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000543 Hom.: 0

Bravo AF: 0.000227

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: The c.1194C>T (p.Thr398=) in MAP2K2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.00097 (19/19528chrs tested) exclusively in individuals of European origin (0.0024; 19/7836). However ExAC includes a warning note, this variant is only covered in 9764 individuals (adjusted allele number = 19528). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site. Regardless, this frequency exceeds the maximal expected frequency of a pathogenic allele (0.0000025) in this gene. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but was cited as Likely Benign by reputable databases/clinical laboratory. Taking together, based on the prevalence in the general population, the synonymous nature of the variant and the lack of predicted effect on splicing, the variant was classified as Benign. -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.1194C>T (p.Thr398=) variant in the MAP2K2 gene is 0.159% (19/7836) 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) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2010

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.92
Dann	Benign	0.72
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

Other links and lift over

dbSNP: rs144850779; hg19: chr19-4090605;