chr4-183253824-G-A

Position:

• chr4-183253824-G-A

Variant summary

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

The NM_024949.6(WWC2):​c.1021G>A​(p.Glu341Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWC2	NM_024949.6	c.1021G>A	p.Glu341Lys	missense_variant	9/23	ENST00000403733.8	NP_079225.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWC2	ENST00000403733.8	c.1021G>A	p.Glu341Lys	missense_variant	9/23	5	NM_024949.6	ENSP00000384222.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Mar 07, 2024

The c.1021G>A (p.E341K) 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 1021, causing the glutamic acid (E) at amino acid position 341 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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.091	T;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.21		Gain of ubiquitination at E341 (P = 0.0203);Gain of ubiquitination at E341 (P = 0.0203);Gain of ubiquitination at E341 (P = 0.0203);.;
MVP		0.63
MPC		0.23
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-184174977; COSMIC: COSV66717432;