Genetic Variant GSDMC:p.Arg474Ser (chr8-129748606-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031415.3(GSDMC):c.1422G>C(p.Arg474Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GSDMC
NM_031415.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.396

Variant links:

Genes affected

GSDMC (HGNC:7151): (gasdermin C) Predicted to enable phosphatidylinositol-4,5-bisphosphate binding activity; phosphatidylinositol-4-phosphate binding activity; and phosphatidylserine binding activity. Predicted to be involved in defense response to bacterium and pyroptosis. Predicted to act upstream of or within intestinal epithelial cell development. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

GSDMC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.0976415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMC	NM_031415.3 link	c.1422G>C	p.Arg474Ser	missense_variant	Exon 14 of 14	ENST00000276708.9	NP_113603.1	Q9BYG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GSDMC	ENST00000276708.9 link	c.1422G>C	p.Arg474Ser	missense_variant	Exon 14 of 14	1	NM_031415.3	ENSP00000276708.4	Q9BYG8
GSDMC	ENST00000522273.5 link	n.767G>C		non_coding_transcript_exon_variant	Exon 8 of 8	1
GSDMC	ENST00000619643.1 link	c.1422G>C	p.Arg474Ser	missense_variant	Exon 13 of 13	2			Q9BYG8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249894

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461226

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1422G>C (p.R474S) alteration is located in exon 14 (coding exon 13) of the GSDMC gene. This alteration results from a G to C substitution at nucleotide position 1422, causing the arginine (R) at amino acid position 474 to be replaced by a serine (S). 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

0.28

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.6

DANN

Benign

0.94

DEOGEN2

Benign

0.0045

T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.68

.;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.080

Sift

Uncertain

0.028

D;.

Sift4G

Uncertain

0.034

D;D

Polyphen

0.68

P;P

Vest4

0.074

MutPred

0.53

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.030

MPC

0.021

ClinPred

0.20

GERP RS

-0.96

Varity_R

0.13

gMVP

0.096

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over