rs10424722

Variant names:

• chr19-4110554-C-G
• rs10424722
• NM_030662.4:c.405G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-4110554-C-G
• chr19-4110554-C-T
• chr19-4110554-C-A

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.405G>C (p.Gly135=) variant in the MAP2K2 gene is 14.69% (1588/10368) 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/CA137935/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.043 (507 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (460 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -0.200
• Publications: 11 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.405G>C	p.Gly135Gly	synonymous	Exon 3 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.405G>C	p.Gly135Gly	synonymous	Exon 3 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.405G>C	p.Gly135Gly	synonymous	Exon 3 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.405G>C	p.Gly135Gly	synonymous	Exon 3 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.405G>C	p.Gly135Gly	synonymous	Exon 3 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6579 AN: 152124 Hom.: 504 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.0116 AC: 2911 AN: 251148 AF XY: 0.00835

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.00859

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00452 AC: 6610 AN: 1461682 Hom.: 460 Cov.: 32 AF XY: 0.00388 AC XY: 2824 AN XY: 727136

African (AFR) AF: 0.152 AC: 5102 AN: 33478

American (AMR) AF: 0.00973 AC: 435 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.0121 AC: 70 AN: 5768

European-Non Finnish (NFE) AF: 0.000325 AC: 361 AN: 1112008

Other (OTH) AF: 0.00997 AC: 602 AN: 60394

GnomAD4 genome AF: 0.0434 AC: 6602 AN: 152242 Hom.: 507 Cov.: 32 AF XY: 0.0404 AC XY: 3010 AN XY: 74436

African (AFR) AF: 0.151 AC: 6268 AN: 41524

American (AMR) AF: 0.0146 AC: 223 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68032

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0133 Hom.: 39

Bravo AF: 0.0492

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	RASopathy (3)
-	-	2	not provided (2)
-	-	1	Cardiofaciocutaneous syndrome 4 (1)
-	-	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	-0.50
CADD	Benign	7.6
DANN	Benign	0.77
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism (auto)

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: rs10424722; hg19: chr19-4110552; COSMIC: COSV53563361;