19-4101032-C-G

Variant names:

• chr19-4101032-C-G
• rs730880511
• NM_030662.4:c.692G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_030662.4(MAP2K2):​c.692G>C​(p.Arg231Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.692G>C	p.Arg231Pro	missense_variant	Exon 6 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.692G>C	p.Arg231Pro	missense_variant	Exon 6 of 9		NP_001427617.1
MAP2K2	NM_001440689.1	c.122G>C	p.Arg41Pro	missense_variant	Exon 4 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.692G>C	p.Arg231Pro	missense_variant	Exon 6 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409508 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 696448

African (AFR) AF: 0.00 AC: 0 AN: 31990

American (AMR) AF: 0.00 AC: 0 AN: 36804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25310

East Asian (EAS) AF: 0.00 AC: 0 AN: 36528

South Asian (SAS) AF: 0.00 AC: 0 AN: 80210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4516

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085626

Other (OTH) AF: 0.00 AC: 0 AN: 58460

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	-0.27	N;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.58		Loss of methylation at R231 (P = 0.0329);.;
MVP		0.92
MPC		1.6
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		0.058	Neutral
Varity_R		0.94
gMVP		0.88
Mutation Taster		=13/87	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: rs730880511; hg19: chr19-4101030;