rs350916

chr19-4094777-G-Achr19-4094777-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_030662.4(MAP2K2):c.1047-279C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 515,488 control chromosomes in the GnomAD database, including 60,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15847 hom., cov: 33)
  • Exomes 𝑓: 0.49 (44388 hom.)
• Consequence: MAP2K2 NM_030662.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.388

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-4094777-G-A is Benign according to our data. Variant chr19-4094777-G-A is described in ClinVar as [Benign]. Clinvar id is 561820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.1047-279C>T		intron_variant		ENST00000262948.10
MAP2K2	XM_006722799.3	c.768-279C>T		intron_variant
MAP2K2	XM_047439100.1	c.477-279C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.1047-279C>T		intron_variant		1	NM_030662.4	P1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67881 AN: 151962 Hom.: 15839 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.487 AC: 177030 AN: 363410 Hom.: 44388 Cov.: 1 AF XY: 0.483 AC XY: 91217 AN XY: 189012

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.557

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.489

Gnomad4 OTH exome AF: 0.482

GnomAD4 genome AF: 0.447 AC: 67913 AN: 152078 Hom.: 15847 Cov.: 33 AF XY: 0.447 AC XY: 33207 AN XY: 74356

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.498

Gnomad4 EAS AF: 0.652

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.470

Alfa AF: 0.480 Hom.: 20326

Bravo AF: 0.447

Asia WGS AF: 0.493 AC: 1716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.0
Dann	Benign	0.76

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: rs350916; hg19: chr19-4094775;