19-4110564-C-T

Position:

• chr19-4110564-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_030662.4(MAP2K2):​c.395G>A​(p.Gly132Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G132V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_030662.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-4110564-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1495968.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 19-4110564-C-T is Pathogenic according to our data. Variant chr19-4110564-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.395G>A	p.Gly132Asp	missense_variant	3/11	ENST00000262948.10
MAP2K2	XM_006722799.3	c.395G>A	p.Gly132Asp	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.395G>A	p.Gly132Asp	missense_variant	3/11	1	NM_030662.4	P1
MAP2K2	ENST00000394867.9	n.834G>A		non_coding_transcript_exon_variant	2/10	5
MAP2K2	ENST00000599345.1	n.592G>A		non_coding_transcript_exon_variant	3/7	5
MAP2K2	ENST00000687128.1	n.834G>A		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiofaciocutaneous syndrome 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 23, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 31040167, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 34184824, 21178588, 36964972) -

RASopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Baylor Genetics

-

Variant classified using ACMG guidelines -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.30	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.048	D;T
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.57		Loss of catalytic residue at P128 (P = 0.0836);.;
MVP		0.96
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906800; hg19: chr19-4110562;