rs763469132

Variant names:

• chr19-4099254-CCTT-C
• rs763469132
• NM_030662.4:c.863_865delAAG

Your query was ambiguous. Multiple possible variants found:

• chr19-4099254-CCTT-C
• chr19-4099254-CCTT-CCTTCTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_030662.4(MAP2K2):​c.863_865delAAG​(p.Glu288del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000255 in 1,605,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MAP2K2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 5.78
• 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: 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

Specifications for MAP2K2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PM4: Nonframeshift variant in NON repetitive region in NM_030662.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-4099254-CCTT-C is Benign according to our data. Variant chr19-4099254-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 503543.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000853 (13/152354) while in subpopulation AMR AF = 0.000653 (10/15310). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 AD gene.

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.863_865delAAG	p.Glu288del	disruptive_inframe_deletion	Exon 7 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440689.1		c.293_295delAAG	p.Glu98del	disruptive_inframe_deletion	Exon 5 of 9	NP_001427618.1
	MAP2K2	NM_001440688.1		c.705+1762_705+1764delAAG		intron	N/A	NP_001427617.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.863_865delAAG	p.Glu288del	disruptive_inframe_deletion	Exon 7 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.863_865delAAG	p.Glu288del	disruptive_inframe_deletion	Exon 7 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.863_865delAAG	p.Glu288del	disruptive_inframe_deletion	Exon 7 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000475 AC: 11 AN: 231466 AF XY: 0.0000634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000388

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1453538 Hom.: 0 AF XY: 0.0000263 AC XY: 19 AN XY: 722548

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.000137 AC: 6 AN: 43710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39368

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1108740

Other (OTH) AF: 0.000117 AC: 7 AN: 60030

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74516

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.000653 AC: 10 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000276

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=69/31	polymorphism

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: rs763469132; hg19: chr19-4099252; COSMIC: COSV53571141;