rs150833333

Variant names:

• chr19-4102379-G-A
• rs150833333
• NM_030662.4:c.525C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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_001440689.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -1.03
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440689.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	NM_030662.4	MANE Select	c.525C>T	p.Ile175Ile	synonymous	Exon 4 of 11	NP_109587.1
	MAP2K2	NM_001440689.1		c.-46C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001427618.1
	MAP2K2	NM_001440688.1		c.525C>T	p.Ile175Ile	synonymous	Exon 4 of 9	NP_001427617.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.525C>T	p.Ile175Ile	synonymous	Exon 4 of 11	ENSP00000262948.4
	MAP2K2	ENST00000945862.1		c.525C>T	p.Ile175Ile	synonymous	Exon 4 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.525C>T	p.Ile175Ile	synonymous	Exon 4 of 11	ENSP00000567225.1

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

GnomAD2 exomes AF: 0.000260 AC: 59 AN: 226846 AF XY: 0.000220

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 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

African (AFR) AF: 0.000569 AC: 19 AN: 33368

American (AMR) AF: 0.000777 AC: 33 AN: 42482

Ashkenazi Jewish (ASJ) AF: 0.000505 AC: 13 AN: 25758

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39282

South Asian (SAS) AF: 0.000238 AC: 20 AN: 83862

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50416

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0000588 AC: 65 AN: 1106164

Other (OTH) AF: 0.000133 AC: 8 AN: 59934

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

African (AFR) AF: 0.000531 AC: 22 AN: 41456

American (AMR) AF: 0.000719 AC: 11 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000416

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		-1.0

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

Other links and lift over

dbSNP: rs150833333; hg19: chr19-4102377;