rs2521760

Variant names:

• chr7-24727864-C-T
• rs2521760
• NM_001127453.2:c.405-8646G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127453.2(GSDME):​c.405-8646G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,230 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1434 hom., cov: 33)
• Consequence: GSDME NM_001127453.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.405-8646G>A		intron_variant	Intron 3 of 9	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.405-8646G>A		intron_variant	Intron 3 of 9		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20701 AN: 152112 Hom.: 1432 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.136 AC: 20722 AN: 152230 Hom.: 1434 Cov.: 33 AF XY: 0.134 AC XY: 9967 AN XY: 74440

African (AFR) AF: 0.148 AC: 6133 AN: 41502

American (AMR) AF: 0.146 AC: 2235 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 274 AN: 3472

East Asian (EAS) AF: 0.0818 AC: 424 AN: 5184

South Asian (SAS) AF: 0.156 AC: 750 AN: 4822

European-Finnish (FIN) AF: 0.116 AC: 1230 AN: 10620

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9344 AN: 68012

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.141 Hom.: 482

Bravo AF: 0.137

Asia WGS AF: 0.111 AC: 387 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.57
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2521760; hg19: chr7-24767483;