19-4101066-T-C

Variant names:

• chr19-4101066-T-C
• rs727504363
• NM_030662.4:c.658A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_030662.4(MAP2K2):​c.658A>G​(p.Ile220Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,437,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I220T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.97
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39847237).
• BP6: Variant 19-4101066-T-C is Benign according to our data. Variant chr19-4101066-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 177860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.658A>G	p.Ile220Val	missense_variant	Exon 6 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.658A>G	p.Ile220Val	missense_variant	Exon 6 of 9		NP_001427617.1
MAP2K2	NM_001440689.1	c.88A>G	p.Ile30Val	missense_variant	Exon 4 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.658A>G	p.Ile220Val	missense_variant	Exon 6 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437404 Hom.: 0 Cov.: 54 AF XY: 0.00000140 AC XY: 1 AN XY: 712922

African (AFR) AF: 0.00 AC: 0 AN: 32766

American (AMR) AF: 0.00 AC: 0 AN: 41034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38138

South Asian (SAS) AF: 0.00 AC: 0 AN: 82776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5464

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1100416

Other (OTH) AF: 0.00 AC: 0 AN: 59442

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 18, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile220Val in exon 6 of MAP2K2: This variant is not expected to have clinical sig nificance because it has been identified in two individuals with clinical featur es of Noonan syndrome, but each individual also carried a pathogenic variant tha t was thought to cause their clinical features. In addition, this variant was s een in an unaffected parent. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.85	L;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.95	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;T
Sift4G	Benign	0.32	T;T
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.48		Loss of catalytic residue at A224 (P = 0.255);.;
MVP		0.67
MPC		0.89
ClinPred		0.65	D
GERP RS		4.2
PromoterAI		-0.025	Neutral
Varity_R		0.50
gMVP		0.33
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs727504363; hg19: chr19-4101064;