4-183240213-A-G

Variant names:

• chr4-183240213-A-G
• rs958276988
• NM_024949.6:c.553A>G

Variant summary

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

The NM_024949.6(WWC2):​c.553A>G​(p.Met185Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,552,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: WWC2 NM_024949.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• 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]

WWC2-AS1 (HGNC:41041): (WWC2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.553A>G	p.Met185Val	missense	Exon 5 of 23	NP_079225.5
	WWC2	NM_001410864.1		c.553A>G	p.Met185Val	missense	Exon 5 of 23	NP_001397793.1	Q6AWC2-6
	WWC2-AS1	NR_126473.1		n.111+311T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWC2	ENST00000403733.8	TSL:5 MANE Select	c.553A>G	p.Met185Val	missense	Exon 5 of 23	ENSP00000384222.3	Q6AWC2-1
	WWC2-AS1	ENST00000511846.1	TSL:1	n.111+311T>C		intron	N/A
	WWC2	ENST00000962606.1		c.553A>G	p.Met185Val	missense	Exon 5 of 23	ENSP00000632665.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152276 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1400004 Hom.: 0 Cov.: 30 AF XY: 0.00000434 AC XY: 3 AN XY: 690524

African (AFR) AF: 0.00 AC: 0 AN: 31616

American (AMR) AF: 0.0000564 AC: 2 AN: 35454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 36058

South Asian (SAS) AF: 0.00 AC: 0 AN: 78540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079768

Other (OTH) AF: 0.0000688 AC: 4 AN: 58144

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74400

⚠️ 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: 41482

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ 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: 0.0000453

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	0.31
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0053	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.41
Sift	Benign	0.072	T
Sift4G	Benign	0.28	T
Polyphen		0.97	D
Vest4		0.58
MutPred		0.30		Gain of glycosylation at S183 (P = 0.0014)
MVP		0.66
MPC		0.078
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.25
Mutation Taster		=79/21	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: rs958276988; hg19: chr4-184161366;