4-183099499-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024949.6(WWC2):​c.8G>A​(p.Arg3Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000886 in 1,354,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: WWC2 NM_024949.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21855173).

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>A	p.Arg3Lys	missense	Exon 1 of 23	NP_079225.5
	WWC2	NM_001410864.1		c.8G>A	p.Arg3Lys	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>A	p.Arg3Lys	missense	Exon 1 of 23	ENSP00000384222.3	Q6AWC2-1
	WWC2	ENST00000962606.1		c.8G>A	p.Arg3Lys	missense	Exon 1 of 23	ENSP00000632665.1
	WWC2	ENST00000448232.6	TSL:5	c.8G>A	p.Arg3Lys	missense	Exon 1 of 23	ENSP00000398577.2	Q6AWC2-6

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151268 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000914 AC: 11 AN: 1203266 Hom.: 0 Cov.: 30 AF XY: 0.0000119 AC XY: 7 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: 0.0000113 AC: 11 AN: 970520

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

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151268 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73852

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67692

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.28
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.076
Sift	Benign	0.055	T
Sift4G	Benign	0.12	T
Polyphen		0.012	B
Vest4		0.24
MutPred		0.29		Gain of methylation at R3 (P = 0.0197)
MVP		0.21
MPC		0.22
ClinPred		0.89	D
GERP RS		3.8
PromoterAI		0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.18
Mutation Taster		=77/23	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;