4-183253936-G-A

Position:

• chr4-183253936-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024949.6(WWC2):​c.1133G>A​(p.Arg378Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WWC2 NM_024949.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

Genes affected

WWC2 (HGNC:24148): (WW and C2 domain containing 2) This gene encodes a member of the WW-and-C2-domain-containing family of proteins. Members of this family have two N-terminal WW domains that mediate binding to target proteins harboring L/PPxY motifs, an internal C2 domain for membrane association, and C-terminal alpha protein kinase C binding sites and class III PDZ domain-interaction motifs. Proteins of this family are able to form homo- and heterodimers and to modulate hippo pathway signaling. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12329325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWC2	NM_024949.6	c.1133G>A	p.Arg378Lys	missense_variant	9/23	ENST00000403733.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWC2	ENST00000403733.8	c.1133G>A	p.Arg378Lys	missense_variant	9/23	5	NM_024949.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.1133G>A (p.R378K) alteration is located in exon 9 (coding exon 9) of the WWC2 gene. This alteration results from a G to A substitution at nucleotide position 1133, causing the arginine (R) at amino acid position 378 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0030	T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	0.93	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.70	N;N;N;N
REVEL	Benign	0.081
Sift	Benign	0.46	T;T;T;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.27	B;.;.;.
Vest4		0.30
MutPred		0.37		Gain of ubiquitination at R378 (P = 0.0066);Gain of ubiquitination at R378 (P = 0.0066);Gain of ubiquitination at R378 (P = 0.0066);.;
MVP		0.37
MPC		0.23
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.17

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: rs1022570028; hg19: chr4-184175089;