rs566450742

Positions:

• chr7-24702804-C-A
• chr7-24702804-C-T

Variant summary

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

The NM_001127453.2(GSDME):​c.1213G>T​(p.Gly405Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.769

Genes affected

GSDME (HGNC:2810): (gasdermin E) Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GSDME (HGNC:):

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/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.1213G>T	p.Gly405Cys	missense_variant	9/10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.1213G>T	p.Gly405Cys	missense_variant	9/10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	.;.;.;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;.;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;.;D;D;D;D
Sift4G	Uncertain	0.042	D;.;T;T;D;D
Polyphen		1.0	D;D;.;.;D;.
Vest4		0.59
MutPred		0.69		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;Loss of loop (P = 0.1242);.;
MVP		0.41
MPC		0.27
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.24
gMVP		0.33

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

Other links and lift over

dbSNP: rs566450742; hg19: chr7-24742423;