10-45727424-G-C

Position:

• chr10-45727424-G-C

Variant summary

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

The NM_001330074.2(WASHC2C):​c.11G>C​(p.Arg4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC2C NM_001330074.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1934242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC2C	NM_001330074.2	c.11G>C	p.Arg4Pro	missense_variant	Exon 2 of 31	ENST00000623400.4	NP_001317003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC2C	ENST00000623400.4	c.11G>C	p.Arg4Pro	missense_variant	Exon 2 of 31	1	NM_001330074.2	ENSP00000485513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Aug 17, 2022

The c.11G>C (p.R4P) alteration is located in exon 2 (coding exon 2) of the FAM21C gene. This alteration results from a G to C substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a proline (P). 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	0.20
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;.;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T;T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;N;N;N;N;.;D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;D;D;D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;T
Polyphen		0.15	.;B;.;.;.;.;.
Vest4		0.22
MutPred		0.17		.;Gain of glycosylation at R4 (P = 0.0364);Gain of glycosylation at R4 (P = 0.0364);Gain of glycosylation at R4 (P = 0.0364);Gain of glycosylation at R4 (P = 0.0364);Gain of glycosylation at R4 (P = 0.0364);Gain of glycosylation at R4 (P = 0.0364);
MVP		0.44
ClinPred		0.69	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-46222872; COSMIC: COSV100313747; COSMIC: COSV100313747;