4-183245423-A-T

Variant names:

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

Variant summary

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

The NM_024949.6(WWC2):​c.610A>T​(p.Lys204*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,398,162 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: WWC2 NM_024949.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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: 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.610A>T	p.Lys204*	stop_gained	Exon 6 of 23	NP_079225.5
	WWC2	NM_001410864.1		c.610A>T	p.Lys204*	stop_gained	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>T	p.Lys204*	stop_gained	Exon 6 of 23	ENSP00000384222.3	Q6AWC2-1
	WWC2	ENST00000962606.1		c.610A>T	p.Lys204*	stop_gained	Exon 6 of 23	ENSP00000632665.1
	WWC2	ENST00000448232.6	TSL:5	c.610A>T	p.Lys204*	stop_gained	Exon 6 of 23	ENSP00000398577.2	Q6AWC2-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000572 AC: 8 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: 0.00 AC: 0 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: 0.00000367 AC: 4 AN: 1088492

Other (OTH) AF: 0.0000695 AC: 4 AN: 57570

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		3.6
Vest4		0.38
GERP RS		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=19/181	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs748143031; hg19: chr4-184166576;