rs2871775

Positions:

• chr1-17019410-A-G

Variant summary

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

The NM_003000.3(SDHB):​c.766-452T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 152,140 control chromosomes in the GnomAD database, including 16,145 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 0.43 (16145 hom., cov: 32)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.766-452T>C		intron_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.712-452T>C		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.766-452T>C		intron_variant		1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65680 AN: 152022 Hom.: 16141 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.432 AC: 65675 AN: 152140 Hom.: 16145 Cov.: 32 AF XY: 0.427 AC XY: 31744 AN XY: 74372

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.460

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.444

Alfa AF: 0.533 Hom.: 44181

Bravo AF: 0.420

Asia WGS AF: 0.360 AC: 1253 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	5.5
DANN	Benign	0.70

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: rs2871775; hg19: chr1-17345905;