chr19-4090424-G-T

Variant names:

• chr19-4090424-G-T
• rs6630
• NM_030662.4:c.*174C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030662.4(MAP2K2):​c.*174C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 656,426 control chromosomes in the GnomAD database, including 7,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3989 hom., cov: 33)
  • Exomes 𝑓: 0.098 (3498 hom.)
• Consequence: MAP2K2 NM_030662.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0610
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-4090424-G-T is Benign according to our data. Variant chr19-4090424-G-T is described in ClinVar as [Benign]. Clinvar id is 1220587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.*174C>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.*174C>A		3_prime_UTR_variant	Exon 9 of 9		NP_001427617.1
MAP2K2	NM_001440689.1	c.*174C>A		3_prime_UTR_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.*174C>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27007 AN: 152126 Hom.: 3988 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0988

Gnomad ASJ AF: 0.0738

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.0978 AC: 49311 AN: 504182 Hom.: 3498 Cov.: 5 AF XY: 0.0963 AC XY: 25739 AN XY: 267352

African (AFR) AF: 0.408 AC: 6075 AN: 14898

American (AMR) AF: 0.0667 AC: 2070 AN: 31034

Ashkenazi Jewish (ASJ) AF: 0.0829 AC: 1378 AN: 16618

East Asian (EAS) AF: 0.000190 AC: 6 AN: 31520

South Asian (SAS) AF: 0.0919 AC: 4952 AN: 53872

European-Finnish (FIN) AF: 0.117 AC: 3725 AN: 31882

Middle Eastern (MID) AF: 0.111 AC: 246 AN: 2224

European-Non Finnish (NFE) AF: 0.0944 AC: 27734 AN: 293832

Other (OTH) AF: 0.110 AC: 3125 AN: 28302

GnomAD4 genome AF: 0.178 AC: 27029 AN: 152244 Hom.: 3989 Cov.: 33 AF XY: 0.174 AC XY: 12921 AN XY: 74440

African (AFR) AF: 0.411 AC: 17079 AN: 41526

American (AMR) AF: 0.0985 AC: 1506 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 256 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0789 AC: 381 AN: 4828

European-Finnish (FIN) AF: 0.104 AC: 1106 AN: 10612

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0926 AC: 6301 AN: 68016

Other (OTH) AF: 0.161 AC: 339 AN: 2108

Alfa AF: 0.0528 Hom.: 50

Bravo AF: 0.187

Asia WGS AF: 0.0540 AC: 190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.91
DANN	Benign	0.71
PhyloP100		0.061
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs6630; hg19: chr19-4090422;