19-4099314-G-C

Variant names:

• chr19-4099314-G-C
• rs368064728
• NM_030662.4:c.806C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP3 PM2 BP5

This summary comes from the ClinGen Evidence Repository: The c.806C>G (p.Pro269Arg) variant in MAP2K2 is absent from gnomAD (PM2). This variant has been observed in an individual with an alternate mechanism of disease (VCV000013329.8; Laboratory for Molecular Medicine internal data; BP5). Four apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time. Computational prediction tools and conservation analysis suggest that the p.Pro269Arg variant may impact the protein (PP3). In summary, the clinical significance of the p.Pro269Arg variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP3, PM2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180914/MONDO:0021060/004

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:1
• Conservation: PhyloP100: 9.94
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.806C>G	p.Pro269Arg	missense_variant	Exon 7 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440689.1	c.236C>G	p.Pro79Arg	missense_variant	Exon 5 of 9		NP_001427618.1
MAP2K2	NM_001440688.1	c.705+1705C>G		intron_variant	Intron 6 of 8		NP_001427617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.806C>G	p.Pro269Arg	missense_variant	Exon 7 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235910 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000949

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1455320 Hom.: 0 Cov.: 33 AF XY: 0.00000829 AC XY: 6 AN XY: 723524

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 85422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1109378

Other (OTH) AF: 0.0000333 AC: 2 AN: 60104

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Uncertain:2

Mar 09, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.806C>G (p.Pro269Arg) variant in MAP2K2 is absent from gnomAD (PM2). This variant has been observed in an individual with an alternate mechanism of disease (VCV000013329.8; Laboratory for Molecular Medicine internal data; BP5). Four apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time. Computational prediction tools and conservation analysis suggest that the p.Pro269Arg variant may impact the protein (PP3). In summary, the clinical significance of the p.Pro269Arg variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP3, PM2, BP5. -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 269 of the MAP2K2 protein (p.Pro269Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 177876). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MAP2K2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Feb 15, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

MAP2K2-related disorder Uncertain:1

Apr 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAP2K2 c.806C>G variant is predicted to result in the amino acid substitution p.Pro269Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-4099312-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Dec 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P269R variant (also known as c.806C>G), located in coding exon 7 of the MAP2K2 gene, results from a C to G substitution at nucleotide position 806. The proline at codon 269 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiofaciocutaneous syndrome 4 Uncertain:1

Feb 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 02, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.3	L;.
PhyloP100		9.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.89	P;.
Vest4		0.72
MVP		0.83
MPC		0.90
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.75
Mutation Taster		=18/82	disease causing

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: rs368064728; hg19: chr19-4099312;