chr19-4110564-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.80

Publications

7 publications found

Variant links:

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

MAP2K2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 CliVar 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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4110564-C-T is described in CliVar as Pathogenic/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 rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4 link	c.395G>A	p.Gly132Asp	missense_variant	Exon 3 of 11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	NM_001440688.1 link	c.395G>A	p.Gly132Asp	missense_variant	Exon 3 of 9		NP_001427617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAP2K2	ENST00000262948.10 link	c.395G>A	p.Gly132Asp	missense_variant	Exon 3 of 11	1	NM_030662.4	ENSP00000262948.4	P36507
MAP2K2	ENST00000394867.9 link	n.834G>A		non_coding_transcript_exon_variant	Exon 2 of 10	5
MAP2K2	ENST00000599345.1 link	n.592G>A		non_coding_transcript_exon_variant	Exon 3 of 7	5
MAP2K2	ENST00000687128.1 link	n.834G>A		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000852

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiofaciocutaneous syndrome 4

Pathogenic:2

Apr 23, 2020

Undiagnosed Diseases Network, NIH

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Apr 26, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Cardiovascular phenotype

Pathogenic:1

Dec 26, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.395G>A (p.G132D) alteration is located in exon 3 (coding exon 3) of the MAP2K2 gene. This alteration results from a G to A substitution at nucleotide position 395, causing the glycine (G) at amino acid position 132 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individuals with developmental delay, learning difficulties, pulmonary stenosis, short stature, absent eyebrows, hyperelastic skin, palmoplantar hyperkeratosis, and/or other clinical features consistent with MAP2K2-related RASopathy (Linden, 2011; Uluda Alkaya, 2021; Gorukmez, 2023; NCBI ClinVar). Another variant at the same codon, c.395G>T (p.G132V), and another variant at the similar codon in the paralog MAP2K1, c.383G>T (p.G128V), have been identified in individual(s) with features consistent with RASopathies (Narumi, 2007; Schulz, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

RASopathy

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

0.30

N;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.95

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

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.85

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over