rs150833333

Positions:

• chr19-4102379-G-A
• chr19-4102379-G-C

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.525C>T (p.Ile175=) variant in the MAP2K2 gene is 0.255% (11/2418) of Latino 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/CA137952/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -1.03

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 (HGNC:):

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.525C>T	p.Ile175Ile	synonymous_variant	4/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_047439100.1	c.-46C>T		5_prime_UTR_premature_start_codon_gain_variant	2/9		XP_047295056.1
MAP2K2	XM_006722799.3	c.525C>T	p.Ile175Ile	synonymous_variant	4/9		XP_006722862.1
MAP2K2	XM_047439100.1	c.-46C>T		5_prime_UTR_variant	2/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.525C>T	p.Ile175Ile	synonymous_variant	4/11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000260 AC: 59 AN: 226846 Hom.: 0 AF XY: 0.000220 AC XY: 27 AN XY: 122648

Gnomad AFR exome AF: 0.000569

Gnomad AMR exome AF: 0.000813

Gnomad ASJ exome AF: 0.000633

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000780

Gnomad OTH exome AF: 0.000882

GnomAD4 exome AF: 0.000111 AC: 161 AN: 1447014 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 78 AN XY: 718554

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.000777

Gnomad4 ASJ exome AF: 0.000505

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.0000588

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74370

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2012	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2018	Variant summary: MAP2K2 c.525C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 252824 control chromosomes. The observed variant frequency is approximately 98.092 fold of 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. To our knowledge, no occurrence of c.525C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2009	- -

RASopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.525C>T (p.Ile175=) variant in the MAP2K2 gene is 0.255% (11/2418) of Latino 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) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 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

Jun 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.81

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: rs150833333; hg19: chr19-4102377;