Genetic Variant WASHC2C:p.Gln9Pro (chr10-45727439-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001330074.2(WASHC2C):c.26A>C(p.Gln9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

WASHC2C
NM_001330074.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.437

Publications

0 publications found

Variant links:

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 links:

ENSG00000290460 (HGNC:):

ENSG00000290460 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059012353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC2C	NM_001330074.2 link	c.26A>C	p.Gln9Pro	missense_variant	Exon 2 of 31	ENST00000623400.4	NP_001317003.1	Q9Y4E1-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC2C	ENST00000623400.4 link	c.26A>C	p.Gln9Pro	missense_variant	Exon 2 of 31	1	NM_001330074.2	ENSP00000485513.1		Q9Y4E1-7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4512

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111428

Other (OTH)

AF:

0.00

AC:

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.26A>C (p.Q9P) alteration is located in exon 2 (coding exon 2) of the FAM21C gene. This alteration results from a A to C substitution at nucleotide position 26, causing the glutamine (Q) at amino acid position 9 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

0.065

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

1.8

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.023

T;T;.;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.72

T;T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.059

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

-0.44

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

N;N;N;N;N;.;N

REVEL

Benign

0.083

Sift

Benign

0.33

T;T;T;T;T;.;T

Sift4G

Benign

0.29

T;T;T;T;T;T;T

Polyphen

0.0

.;B;.;.;.;.;.

Vest4

0.15

MutPred

0.051

.;Gain of glycosylation at Q9 (P = 0.101);Gain of glycosylation at Q9 (P = 0.101);Gain of glycosylation at Q9 (P = 0.101);Gain of glycosylation at Q9 (P = 0.101);Gain of glycosylation at Q9 (P = 0.101);Gain of glycosylation at Q9 (P = 0.101);

MVP

0.061

ClinPred

0.54

GERP RS

0.86

PromoterAI

0.063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.32

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over