rs2305479

Positions:

• chr17-39905964-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001165958.2(GSDMB):​c.910G>A​(p.Gly304Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,612,868 control chromosomes in the GnomAD database, including 182,933 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (12844 hom., cov: 31)
  • Exomes 𝑓: 0.48 (170089 hom.)
• Consequence: GSDMB NM_001165958.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115

Genes affected

GSDMB (HGNC:23690): (gasdermin B) This gene encodes a member of the gasdermin-domain containing protein family. Other gasdermin-family genes are implicated in the regulation of apoptosis in epithelial cells, and are linked to cancer. Alternative splicing and the use of alternative promoters results in multiple transcript variants. Additional variants have been described, but they are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to be protein-coding. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.8554477E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMB	NM_001165958.2	c.910G>A	p.Gly304Arg	missense_variant	9/11	ENST00000418519.6	NP_001159430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDMB	ENST00000418519.6	c.910G>A	p.Gly304Arg	missense_variant	9/11	5	NM_001165958.2	ENSP00000415049	P2

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58815 AN: 151814 Hom.: 12829 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.427 AC: 107075 AN: 250904 Hom.: 24319 AF XY: 0.435 AC XY: 58936 AN XY: 135614

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.255

Gnomad SAS exome AF: 0.385

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.476 AC: 695936 AN: 1460936 Hom.: 170089 Cov.: 41 AF XY: 0.474 AC XY: 344706 AN XY: 726824

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.441

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.550

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.442

GnomAD4 genome AF: 0.387 AC: 58855 AN: 151932 Hom.: 12844 Cov.: 31 AF XY: 0.389 AC XY: 28907 AN XY: 74250

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.392

Alfa AF: 0.460 Hom.: 36117

Bravo AF: 0.358

TwinsUK AF: 0.497 AC: 1843

ALSPAC AF: 0.506 AC: 1951

ESP6500AA AF: 0.184 AC: 811

ESP6500EA AF: 0.481 AC: 4139

ExAC AF: 0.422 AC: 51250

Asia WGS AF: 0.385 AC: 1337 AN: 3478

EpiCase AF: 0.487

EpiControl AF: 0.479

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.50	.;T;.;T;T;T
MetaRNN	Benign	0.000059	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.3	.;D;D;.;D;D
REVEL	Benign	0.042
Sift	Benign	0.13	.;T;T;.;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;B;B;B;.;D
Vest4		0.079
MPC		0.63
ClinPred		0.10	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs2305479; hg19: chr17-38062217; COSMIC: COSV58779510; COSMIC: COSV58779510;