10-45727465-G-T

Position:

• chr10-45727465-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367411.1(WASHC2C):​c.-166G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,954 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WASHC2C NM_001367411.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

WASHC2C (HGNC:23414): (WASH complex subunit 2C) Enables phosphatidylinositol phosphate binding activity; phosphatidylinositol-3,4-bisphosphate binding activity; and retromer complex binding activity. Involved in several processes, including endosomal transport; negative regulation of barbed-end actin filament capping; and regulation of substrate adhesion-dependent cell spreading. Located in cytosol; early endosome; and nucleolus. Part of WASH complex. [provided by Alliance of Genome Resources, Apr 2022]

WASHC2C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24484643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC2C	NM_001330074.2	c.52G>T	p.Val18Leu	missense_variant	2/31	ENST00000623400.4	NP_001317003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC2C	ENST00000623400.4	c.52G>T	p.Val18Leu	missense_variant	2/31	1	NM_001330074.2	ENSP00000485513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457954 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Dec 02, 2021

The c.52G>T (p.V18L) alteration is located in exon 2 (coding exon 2) of the FAM21C gene. This alteration results from a G to T substitution at nucleotide position 52, causing the valine (V) at amino acid position 18 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	0.36
BayesDel_addAF	Benign	0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T;.;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D;D;T;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;N;N;N;N;.;N
REVEL	Benign	0.081
Sift	Uncertain	0.017	D;T;T;T;T;.;D
Sift4G	Benign	0.21	T;T;T;T;T;T;T
Polyphen		0.33	.;B;.;.;.;.;.
Vest4		0.11
MutPred		0.14		.;Gain of glycosylation at P17 (P = 0.1452);Gain of glycosylation at P17 (P = 0.1452);Gain of glycosylation at P17 (P = 0.1452);Gain of glycosylation at P17 (P = 0.1452);Gain of glycosylation at P17 (P = 0.1452);Gain of glycosylation at P17 (P = 0.1452);
MVP		0.12
ClinPred		0.67	D
GERP RS		3.4
Varity_R		0.20
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs750336718; hg19: chr10-46222913;