rs2235931

Positions:

• chr1-17023460-G-A
• chr1-17023460-G-C

Variant summary

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

The NM_003000.3(SDHB):​c.642+513C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,162 control chromosomes in the GnomAD database, including 3,623 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 0.20 (3623 hom., cov: 33)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.642+513C>T		intron_variant		ENST00000375499.8
SDHB	NM_001407361.1	c.588+513C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.642+513C>T		intron_variant		1	NM_003000.3	P1
SDHB	ENST00000463045.3	c.471+513C>T		intron_variant		3
SDHB	ENST00000491274.6	c.600+513C>T		intron_variant		5
SDHB	ENST00000485515.5	n.576+513C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30996 AN: 152044 Hom.: 3618 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.210

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

GnomAD4 genome AF: 0.204 AC: 31023 AN: 152162 Hom.: 3623 Cov.: 33 AF XY: 0.212 AC XY: 15770 AN XY: 74366

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.209

Alfa AF: 0.0944 Hom.: 141

Bravo AF: 0.203

Asia WGS AF: 0.332 AC: 1154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.4
DANN	Benign	0.52

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: rs2235931; hg19: chr1-17349955;