4-183248811-T-C

Variant names:

• chr4-183248811-T-C
• rs1225224400
• NM_024949.6:c.830T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024949.6(WWC2):​c.830T>C​(p.Leu277Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,210 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WWC2 NM_024949.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWC2	NM_024949.6	c.830T>C	p.Leu277Pro	missense_variant	Exon 7 of 23	ENST00000403733.8	NP_079225.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWC2	ENST00000403733.8	c.830T>C	p.Leu277Pro	missense_variant	Exon 7 of 23	5	NM_024949.6	ENSP00000384222.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451210 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 720644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.830T>C (p.L277P) alteration is located in exon 7 (coding exon 7) of the WWC2 gene. This alteration results from a T to C substitution at nucleotide position 830, causing the leucine (L) at amino acid position 277 to be replaced by a proline (P). 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	0.096
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;T;T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.46		Gain of disorder (P = 0.0273);Gain of disorder (P = 0.0273);Gain of disorder (P = 0.0273);
MVP		0.55
MPC		0.26
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1225224400; hg19: chr4-184169964;