chr17-39909987-T-C

Variant names:

• chr17-39909987-T-C
• rs2290400
• NM_001165958.2:c.408-63A>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001165958.2(GSDMB):c.408-63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.483 (AC=611,763) in the gnomAD database across 1,265,582 control chromosomes, including 150,310 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.5. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.48 (17511 hom., cov: 32)
  • Exomes 𝑓: 0.48 (132799 hom.)
• Consequence: GSDMB NM_001165958.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 181 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4998 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001165958.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GSDMB NM_001165958.2	MANE Select	c.408-63A>G	intron	Intron 3 of 10	Prot: NP_001159430.1 UniProt:
	GSDMB NM_001388420.1		c.408-63A>G	intron	Intron 2 of 9	Prot: NP_001375349.1 UniProt:
	GSDMB NM_001165959.2		c.408-63A>G	intron	Intron 3 of 9	Prot: NP_001159431.1 UniProt:

GSDMB NM_001165958.2

MANE Select

HGVSc / HGVSpc.408-63A>G

Exon rankIntron 3 of 10

intron

Prot: NP_001159430.1UniProt: Q8TAX9-4

GSDMB NM_001388420.1

HGVSc / HGVSpc.408-63A>G

Exon rankIntron 2 of 9

intron

Prot: NP_001375349.1UniProt: Q8TAX9-4

GSDMB NM_001165959.2

HGVSc / HGVSpc.408-63A>G

Exon rankIntron 3 of 9

intron

Prot: NP_001159431.1UniProt: Q8TAX9-6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GSDMB ENST00000418519.6	TSL:5MANE Select	c.408-63A>G	intron	Intron 3 of 10	Prot: ENSP00000415049.1 UniProt:
	GSDMB ENST00000360317.7	TSL:1	c.408-63A>G	intron	Intron 2 of 9	Prot: ENSP00000353465.3 UniProt:
	GSDMB ENST00000394179.5	TSL:1	c.408-63A>G	intron	Intron 2 of 8	Prot: ENSP00000377733.2 UniProt:

GSDMB ENST00000418519.6

TSL:5MANE Select

HGVSc / HGVSpc.408-63A>G

Exon rankIntron 3 of 10

intron

Prot: ENSP00000415049.1UniProt: Q8TAX9-4

GSDMB ENST00000360317.7

TSL:1

HGVSc / HGVSpc.408-63A>G

Exon rankIntron 2 of 9

intron

Prot: ENSP00000353465.3UniProt: Q8TAX9-4

GSDMB ENST00000394179.5

TSL:1

HGVSc / HGVSpc.408-63A>G

Exon rankIntron 2 of 8

intron

Prot: ENSP00000377733.2UniProt: Q8TAX9-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.477	AC:72467	Hom:17464	AN:151890	Cov:32
GnomAD4 exome	AF: 0.484	AC:539188	Hom:132799	AN:1113574	Cov:
GnomAD4 genome	AF: 0.477	AC:72575	Hom:17511	AN:152008	Cov:32
TOPMed (Bravo)	AF: 0.461	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.486	AC:325458	Hom:79329	AN:670310	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.439	AC:1029	Hom:228	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.273	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.513	AC:154	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.417	AC:1448	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.265	AC:1920	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.557	AC:98	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.266	AC:32539	Hom:4343	AN:122366	Cov:
UK10K	AF: 0.506	AC:3824	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.259	AC:2318	Hom:311	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.381	25414	66622	0.396	50263	126826

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.6
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.71
DANN	Benign	0.35
GPN-Star LLR	N/A	5.4
GPN-Star score	N/A	0.33
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.2

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2290400;

hg19: chr17-38066240;

COSMIC: COSV58783257;

COSMIC: COSV58783257;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar