rs377101954

chr19-4102330-G-Achr19-4102330-G-Cchr19-4102330-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030662.4(MAP2K2):c.528+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000727 in 1,489,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (3 hom.)
• Consequence: MAP2K2 NM_030662.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.310

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-4102330-G-A is Benign according to our data. Variant chr19-4102330-G-A is described in ClinVar as [Benign]. Clinvar id is 261930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000643 (98/152314) while in subpopulation AMR AF= 0.000981 (15/15294). AF 95% confidence interval is 0.000742. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.528+46C>T		intron_variant		ENST00000262948.10
MAP2K2	XM_006722799.3	c.528+46C>T		intron_variant
MAP2K2	XM_047439100.1	c.-43+46C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.528+46C>T		intron_variant		1	NM_030662.4	P1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000503 AC: 82 AN: 162864 Hom.: 1 AF XY: 0.000541 AC XY: 47 AN XY: 86894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000314

Gnomad ASJ exome AF: 0.000929

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000872

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.000736 AC: 984 AN: 1336850 Hom.: 3 Cov.: 21 AF XY: 0.000691 AC XY: 459 AN XY: 663858

Gnomad4 AFR exome AF: 0.000161

Gnomad4 AMR exome AF: 0.000468

Gnomad4 ASJ exome AF: 0.000927

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000883

Gnomad4 OTH exome AF: 0.000570

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74476

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.000752

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.62
Dann	Benign	0.47

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: rs377101954; hg19: chr19-4102328; COSMIC: COSV104543656; COSMIC: COSV104543656;