chr19-4123844-G-C

Variant names:

• chr19-4123844-G-C
• rs1555699410
• NM_030662.4:c.32C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030662.4(MAP2K2):​c.32C>G​(p.Ala11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,298 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A11A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.165
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16201833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.32C>G	p.Ala11Gly	missense_variant	Exon 1 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.32C>G	p.Ala11Gly	missense_variant	Exon 1 of 9		NP_001427617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.32C>G	p.Ala11Gly	missense_variant	Exon 1 of 11	1	NM_030662.4	ENSP00000262948.4
MAP2K2	ENST00000599345.1	n.229C>G		non_coding_transcript_exon_variant	Exon 1 of 7	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377298 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 681360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29060

American (AMR) AF: 0.00 AC: 0 AN: 35846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24204

East Asian (EAS) AF: 0.00 AC: 0 AN: 32690

South Asian (SAS) AF: 0.00 AC: 0 AN: 77080

European-Finnish (FIN) AF: 0.0000232 AC: 1 AN: 43012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073844

Other (OTH) AF: 0.00 AC: 0 AN: 56802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: in Gnomad 19:4123841 G / C-not present, but coverage not ideal; not in ClinVar, HGMD, or Google search; predicted benign, gene not in many animals, but well-conserved in those -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.17
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.63	N
REVEL	Uncertain	0.32
Sift	Benign	0.40	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.20		Loss of stability (P = 0.0842);
MVP		0.63
MPC		0.44
ClinPred		0.33	T
GERP RS		3.9
PromoterAI		-0.012	Neutral
Varity_R		0.33
gMVP		0.22
Mutation Taster		=77/23	polymorphism

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: rs1555699410; hg19: chr19-4123841;