12-108210300-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014653.4(WSCD2):c.677G>T(p.Arg226Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WSCD2 NM_014653.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

Genes affected

WSCD2 (HGNC:29117): (WSC domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC124903077 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WSCD2	NM_014653.4	c.677G>T	p.Arg226Leu	missense_variant	4/9	ENST00000547525.6
LOC124903077	XR_007063583.1	n.183-19281C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WSCD2	ENST00000547525.6	c.677G>T	p.Arg226Leu	missense_variant	4/9	1	NM_014653.4	P1
WSCD2	ENST00000332082.8	c.677G>T	p.Arg226Leu	missense_variant	5/10	1		P1
WSCD2	ENST00000549903.1	c.677G>T	p.Arg226Leu	missense_variant	3/9	5
WSCD2	ENST00000551638.5	c.218G>T	p.Arg73Leu	missense_variant	3/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425888 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 2 AN XY: 707190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2023

The c.677G>T (p.R226L) alteration is located in exon 4 (coding exon 3) of the WSCD2 gene. This alteration results from a G to T substitution at nucleotide position 677, causing the arginine (R) at amino acid position 226 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.18	B;.;B;.
Vest4		0.80
MutPred		0.47		Gain of catalytic residue at S230 (P = 0.0135);.;Gain of catalytic residue at S230 (P = 0.0135);Gain of catalytic residue at S230 (P = 0.0135);
MVP		0.085
MPC		0.59
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.49
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374953285; hg19: chr12-108604077;