NM_030662.4:c.603C>T

Variant names:

• chr19-4101121-G-A
• rs148291450
• NM_030662.4:c.603C>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.603C>T (p.Leu201=) variant in the MAP2K2 gene is 0.191% (18/6102) of African 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/CA137956/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.577
• Publications: 0 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: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 4

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN 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_030662.4. 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.603C>T	p.Leu201Leu	synonymous	Exon 6 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.603C>T	p.Leu201Leu	synonymous	Exon 6 of 9	NP_001427617.1
	MAP2K2	NM_001440689.1		c.33C>T	p.Leu11Leu	synonymous	Exon 4 of 9	NP_001427618.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.603C>T	p.Leu201Leu	synonymous	Exon 6 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.603C>T	p.Leu201Leu	synonymous	Exon 6 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.603C>T	p.Leu201Leu	synonymous	Exon 6 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000193 AC: 46 AN: 238866 AF XY: 0.000186

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.0000893

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000839

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000113 AC: 164 AN: 1455872 Hom.: 0 Cov.: 54 AF XY: 0.000112 AC XY: 81 AN XY: 723642

African (AFR) AF: 0.00210 AC: 70 AN: 33330

American (AMR) AF: 0.0000681 AC: 3 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39336

South Asian (SAS) AF: 0.000118 AC: 10 AN: 84934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000640 AC: 71 AN: 1109428

Other (OTH) AF: 0.000150 AC: 9 AN: 60126

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74446

African (AFR) AF: 0.00226 AC: 94 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000574

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	MAP2K2-related disorder (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.58
PromoterAI		-0.015	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148291450; hg19: chr19-4101119;