rs2305480

Positions:

• chr17-39905943-G-A

Variant summary

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

The NM_001165958.2(GSDMB):​c.931C>T​(p.Pro311Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,612,900 control chromosomes in the GnomAD database, including 155,927 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 0.35 (10857 hom., cov: 31)
  • Exomes 𝑓: 0.44 (145070 hom.)
• Consequence: GSDMB NM_001165958.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433

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=1.2097034E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMB	NM_001165958.2	c.931C>T	p.Pro311Ser	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.931C>T	p.Pro311Ser	missense_variant	9/11	5	NM_001165958.2	ENSP00000415049	P2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53353 AN: 151802 Hom.: 10846 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.356

GnomAD3 exomes AF: 0.396 AC: 99349 AN: 251044 Hom.: 20968 AF XY: 0.404 AC XY: 54815 AN XY: 135676

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.255

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.440 AC: 642751 AN: 1460978 Hom.: 145070 Cov.: 38 AF XY: 0.439 AC XY: 318713 AN XY: 726816

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.330

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.464

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.351 AC: 53390 AN: 151922 Hom.: 10857 Cov.: 31 AF XY: 0.355 AC XY: 26343 AN XY: 74246

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.412

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.354

Alfa AF: 0.428 Hom.: 36999

Bravo AF: 0.325

TwinsUK AF: 0.457 AC: 1695

ALSPAC AF: 0.469 AC: 1807

ESP6500AA AF: 0.147 AC: 647

ESP6500EA AF: 0.443 AC: 3808

ExAC AF: 0.390 AC: 47337

Asia WGS AF: 0.365 AC: 1267 AN: 3478

EpiCase AF: 0.451

EpiControl AF: 0.444

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.20
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.50	.;T;.;T;T;T
MetaRNN	Benign	0.00012	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.8	.;D;D;.;D;D
REVEL	Benign	0.032
Sift	Benign	0.90	.;T;T;.;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.34	B;B;B;B;.;B
Vest4		0.073
MPC		0.21
ClinPred		0.070	T
GERP RS		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.29

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: rs2305480; hg19: chr17-38062196; COSMIC: COSV58779652; COSMIC: COSV58779652;