19-4090639-G-T

Variant names:

• chr19-4090639-G-T
• rs144383241
• NM_030662.4:c.1162C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_030662.4(MAP2K2):​c.1162C>A​(p.Arg388Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R388R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 19-4090639-G-T is Benign according to our data. Variant chr19-4090639-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1737151.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.1162C>A	p.Arg388Arg	synonymous_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.883C>A	p.Arg295Arg	synonymous_variant	Exon 9 of 9		NP_001427617.1
MAP2K2	NM_001440689.1	c.592C>A	p.Arg198Arg	synonymous_variant	Exon 9 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.1162C>A	p.Arg388Arg	synonymous_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000608 AC: 1 AN: 164554 AF XY: 0.00

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403656 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 692960

African (AFR) AF: 0.0000314 AC: 1 AN: 31882

American (AMR) AF: 0.00 AC: 0 AN: 36290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 36228

South Asian (SAS) AF: 0.00 AC: 0 AN: 79670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081908

Other (OTH) AF: 0.00 AC: 0 AN: 58166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Oct 02, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.48
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		1.1
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

Other links and lift over

dbSNP: rs144383241; hg19: chr19-4090637;