rs2235930

Positions:

• chr1-17023648-G-A
• chr1-17023648-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003000.3(SDHB):​c.642+325C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 152,026 control chromosomes in the GnomAD database, including 21,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.51 (21272 hom., cov: 32)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.252

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-17023648-G-A is Benign according to our data. Variant chr1-17023648-G-A is described in ClinVar as [Benign]. Clinvar id is 695745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.642+325C>T		intron_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.588+325C>T		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.642+325C>T		intron_variant		1	NM_003000.3	ENSP00000364649	P1
SDHB	ENST00000463045.3	c.471+325C>T		intron_variant		3		ENSP00000481376
SDHB	ENST00000491274.6	c.600+325C>T		intron_variant		5		ENSP00000480482
SDHB	ENST00000485515.5	n.576+325C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77750 AN: 151910 Hom.: 21225 Cov.: 32

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.481

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

GnomAD4 genome AF: 0.512 AC: 77851 AN: 152026 Hom.: 21272 Cov.: 32 AF XY: 0.517 AC XY: 38403 AN XY: 74288

Gnomad4 AFR AF: 0.698

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.694

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.487

Alfa AF: 0.454 Hom.: 1975

Bravo AF: 0.522

Asia WGS AF: 0.622 AC: 2163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.61

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: rs2235930; hg19: chr1-17350143; COSMIC: COSV64964957; COSMIC: COSV64964957;