4-183099499-G-C

Variant names:

• chr4-183099499-G-C
• rs1043877211
• NM_024949.6:c.8G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024949.6(WWC2):​c.8G>C​(p.Arg3Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,203,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R3K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: WWC2 NM_024949.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32320192).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024949.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWC2	NM_024949.6	MANE Select	c.8G>C	p.Arg3Thr	missense	Exon 1 of 23	NP_079225.5
	WWC2	NM_001410864.1		c.8G>C	p.Arg3Thr	missense	Exon 1 of 23	NP_001397793.1	Q6AWC2-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWC2	ENST00000403733.8	TSL:5 MANE Select	c.8G>C	p.Arg3Thr	missense	Exon 1 of 23	ENSP00000384222.3	Q6AWC2-1
	WWC2	ENST00000962606.1		c.8G>C	p.Arg3Thr	missense	Exon 1 of 23	ENSP00000632665.1
	WWC2	ENST00000448232.6	TSL:5	c.8G>C	p.Arg3Thr	missense	Exon 1 of 23	ENSP00000398577.2	Q6AWC2-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000249 AC: 3 AN: 1203266 Hom.: 0 Cov.: 30 AF XY: 0.00000509 AC XY: 3 AN XY: 589784

African (AFR) AF: 0.00 AC: 0 AN: 24414

American (AMR) AF: 0.00 AC: 0 AN: 21332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18660

East Asian (EAS) AF: 0.00 AC: 0 AN: 24992

South Asian (SAS) AF: 0.00 AC: 0 AN: 51536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4588

European-Non Finnish (NFE) AF: 0.00000309 AC: 3 AN: 970520

Other (OTH) AF: 0.00 AC: 0 AN: 47002

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.60	P
Vest4		0.42
MutPred		0.30		Loss of MoRF binding (P = 0.0085)
MVP		0.33
MPC		0.26
ClinPred		0.88	D
GERP RS		3.8
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.21
Mutation Taster		=61/39	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: rs1043877211; hg19: chr4-184020652;