Genetic Variant GSDMC:p.Gln382Pro (chr8-129750058-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_031415.3(GSDMC):c.1145A>C(p.Gln382Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GSDMC
NM_031415.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.42

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 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
GSDMC	NM_031415.3 link	c.1145A>C	p.Gln382Pro	missense_variant	Exon 12 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.1145A>C	p.Gln382Pro	missense_variant	Exon 12 of 14	1	NM_031415.3	ENSP00000276708.4	Q9BYG8
GSDMC	ENST00000522273.5 link	n.490A>C		non_coding_transcript_exon_variant	Exon 6 of 8	1
GSDMC	ENST00000619643.1 link	c.1145A>C	p.Gln382Pro	missense_variant	Exon 11 of 13	2			Q9BYG8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1145A>C (p.Q382P) alteration is located in exon 12 (coding exon 11) of the GSDMC gene. This alteration results from a A to C substitution at nucleotide position 1145, causing the glutamine (Q) at amino acid position 382 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

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.3

DANN

Benign

0.97

DEOGEN2

Benign

0.0056

T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.38

.;T

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.1

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.18

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.026

D;D

Polyphen

1.0

D;D

Vest4

0.57

MutPred

0.54

Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);

MVP

0.014

MPC

0.15

ClinPred

0.43

GERP RS

-9.2

Varity_R

0.25

gMVP

0.41

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