rs748143031

Variant names:

• chr4-183245423-A-G
• rs748143031
• NM_024949.6:c.610A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-183245423-A-G
• chr4-183245423-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024949.6(WWC2):​c.610A>G​(p.Lys204Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,550,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K204N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: WWC2 NM_024949.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05779639).

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.610A>G	p.Lys204Glu	missense	Exon 6 of 23	NP_079225.5
	WWC2	NM_001410864.1		c.610A>G	p.Lys204Glu	missense	Exon 6 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.610A>G	p.Lys204Glu	missense	Exon 6 of 23	ENSP00000384222.3	Q6AWC2-1
	WWC2	ENST00000962606.1		c.610A>G	p.Lys204Glu	missense	Exon 6 of 23	ENSP00000632665.1
	WWC2	ENST00000448232.6	TSL:5	c.610A>G	p.Lys204Glu	missense	Exon 6 of 23	ENSP00000398577.2	Q6AWC2-6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000329 AC: 6 AN: 182486 AF XY: 0.0000405

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000501 AC: 7 AN: 1398162 Hom.: 0 Cov.: 30 AF XY: 0.00000577 AC XY: 4 AN XY: 693656

African (AFR) AF: 0.00 AC: 0 AN: 29600

American (AMR) AF: 0.00 AC: 0 AN: 28890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23010

East Asian (EAS) AF: 0.000186 AC: 7 AN: 37720

South Asian (SAS) AF: 0.00 AC: 0 AN: 75986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088492

Other (OTH) AF: 0.00 AC: 0 AN: 57570

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00030	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.078
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.18		Loss of ubiquitination at K204 (P = 0.002)
MVP		0.061
MPC		0.036
ClinPred		0.066	T
GERP RS		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.098
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748143031; hg19: chr4-184166576;