rs116988721

chr19-4117401-C-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.303+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,610,442 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (126 hom.)
• Consequence: MAP2K2 NM_030662.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.434

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 19-4117401-C-T is Benign according to our data. Variant chr19-4117401-C-T is described in ClinVar as [Benign]. Clinvar id is 40789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4117401-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00872 (1328/152336) while in subpopulation NFE AF= 0.0136 (927/68030). AF 95% confidence interval is 0.0129. There are 10 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1327 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.303+18G>A		intron_variant		ENST00000262948.10
MAP2K2	XM_006722799.3	c.303+18G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.303+18G>A		intron_variant		1	NM_030662.4	P1
MAP2K2	ENST00000394867.9	n.742+18G>A		intron_variant, non_coding_transcript_variant		5
MAP2K2	ENST00000599345.1	n.500+18G>A		intron_variant, non_coding_transcript_variant		5
MAP2K2	ENST00000687128.1	n.742+18G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00872 AC: 1327 AN: 152218 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00890 AC: 2205 AN: 247876 Hom.: 17 AF XY: 0.00902 AC XY: 1215 AN XY: 134658

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00746

Gnomad ASJ exome AF: 0.00652

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00239

Gnomad FIN exome AF: 0.00960

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0121 AC: 17584 AN: 1458106 Hom.: 126 Cov.: 34 AF XY: 0.0120 AC XY: 8693 AN XY: 725420

Gnomad4 AFR exome AF: 0.00240

Gnomad4 AMR exome AF: 0.00710

Gnomad4 ASJ exome AF: 0.00640

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00967

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00872 AC: 1328 AN: 152336 Hom.: 10 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74490

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0107 Hom.: 3

Bravo AF: 0.00817

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: MAP2K2 c.303+18G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site. One predicts the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0089 in 247876 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 3558-folds over the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiofaciocutaneous syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.22
Dann	Benign	0.62

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: rs116988721; hg19: chr19-4117399; COSMIC: COSV53568032;