chr10-45728877-C-A

Variant names:

• chr10-45728877-C-A
• rs777777260
• NM_001330074.2:c.142C>A

Variant summary

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

The NM_001330074.2(WASHC2C):​c.142C>A​(p.Gln48Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,272 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: 0.0000048 (0 hom.)
• Consequence: WASHC2C NM_001330074.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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]

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 rank	MANE	Protein	UniProt
WASHC2C	NM_001330074.2	c.142C>A	p.Gln48Lys	missense_variant	Exon 3 of 31	ENST00000623400.4	NP_001317003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC2C	ENST00000623400.4	c.142C>A	p.Gln48Lys	missense_variant	Exon 3 of 31	1	NM_001330074.2	ENSP00000485513.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000816 AC: 2 AN: 244988 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000684

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461272 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142C>A (p.Q48K) alteration is located in exon 3 (coding exon 3) of the FAM21C gene. This alteration results from a C to A substitution at nucleotide position 142, causing the glutamine (Q) at amino acid position 48 to be replaced by a lysine (K). 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	Benign	0.29
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.36	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.065	T;T;T;T;.
Sift4G	Uncertain	0.046	D;T;D;D;D
Polyphen		0.71	P;.;.;.;.
Vest4		0.21
MutPred		0.37		Gain of ubiquitination at Q48 (P = 0.0258);Gain of ubiquitination at Q48 (P = 0.0258);Gain of ubiquitination at Q48 (P = 0.0258);Gain of ubiquitination at Q48 (P = 0.0258);Gain of ubiquitination at Q48 (P = 0.0258);
MVP		0.22
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.46
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 29

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

Publications

LitVar

Other links and lift over

dbSNP: rs777777260; hg19: chr10-46224325;