10-45728918-C-G

Position:

• chr10-45728918-C-G

Variant summary

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

The NM_001367411.1(WASHC2C):​c.-79C>G 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 0.00000137 in 1,461,648 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: 31)
  • Exomes 𝑓: 0.0000014 (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: 0.453

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=0.19313398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WASHC2C	NM_001330074.2	c.183C>G	p.Ile61Met	missense_variant	3/31	ENST00000623400.4	NP_001317003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WASHC2C	ENST00000623400.4	c.183C>G	p.Ile61Met	missense_variant	3/31	1	NM_001330074.2	ENSP00000485513.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461648 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

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

Oct 14, 2023

The c.183C>G (p.I61M) alteration is located in exon 3 (coding exon 3) of the FAM21C gene. This alteration results from a C to G substitution at nucleotide position 183, causing the isoleucine (I) at amino acid position 61 to be replaced by a methionine (M). 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	0.34
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.45	T
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N;N;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.031	D;D;D;D;.
Sift4G	Uncertain	0.028	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.37
MutPred		0.26		Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);
MVP		0.21
ClinPred		0.89	D
GERP RS		4.0
Varity_R		0.43
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-46224366;