rs369925884

Positions:

• chr19-4110539-G-A
• chr19-4110539-G-C
• chr19-4110539-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.420C>T (p.Asp140=) variant in the MAP2K2 gene is 0.271% (32/8604) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137938/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.0370

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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.420C>T	p.Asp140Asp	synonymous_variant	3/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.420C>T	p.Asp140Asp	synonymous_variant	3/9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.420C>T	p.Asp140Asp	synonymous_variant	3/11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000394867.9	n.859C>T		non_coding_transcript_exon_variant	2/10	5
MAP2K2	ENST00000599345.1	n.617C>T		non_coding_transcript_exon_variant	3/7	5
MAP2K2	ENST00000687128.1	n.859C>T		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251120 Hom.: 1 AF XY: 0.000324 AC XY: 44 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000333 AC: 487 AN: 1461606 Hom.: 2 Cov.: 32 AF XY: 0.000309 AC XY: 225 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00597

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74444

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000204

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.420C>T (p.Asp140=) variant in the MAP2K2 gene is 0.271% (32/8604) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 14, 2016

Variant summary: The MAP2K2 c.420C>T (p.Asp140Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 45/121454 control chromosomes (1 homozygote) at a frequency of 0.0003705, which is approximately 148 times the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. The variant has been reported in patients/families with metachondromatosis, autism and carcinoma of large intestine, without strong evidence for pathogenicity (COSMIC, Bowen_2011, Kelleher_2012). In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2022

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. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.5
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs369925884; hg19: chr19-4110537; COSMIC: COSV53562348;