19-4101066-T-C

Position:

• chr19-4101066-T-C

Variant summary

Our verdict is Likely benign. Variant got -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 (★). Synonymous variant affecting the same amino acid position (i.e. I220I) has been classified as Benign.

• 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

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.658A>G	p.Ile220Val	missense_variant	6/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.658A>G	p.Ile220Val	missense_variant	6/9		XP_006722862.1
MAP2K2	XM_047439100.1	c.88A>G	p.Ile30Val	missense_variant	4/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.658A>G	p.Ile220Val	missense_variant	6/11	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 18, 2013

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;.
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
Varity_R		0.50
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504363; hg19: chr19-4101064;