rs1022580

Positions:

• chr1-17033181-C-A
• chr1-17033181-C-G

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.201-36G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,503,420 control chromosomes in the GnomAD database, including 710,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69693 hom., cov: 32)
  • Exomes 𝑓: 0.97 (640992 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.294

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=-0.9).
• BP6: Variant 1-17033181-C-A is Benign according to our data. Variant chr1-17033181-C-A is described in ClinVar as [Benign]. Clinvar id is 258889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.201-36G>T		intron_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.201-36G>T		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.201-36G>T		intron_variant		1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes AF: 0.956 AC: 145515 AN: 152160 Hom.: 69638 Cov.: 32

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.953

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.973

Gnomad OTH AF: 0.950

GnomAD3 exomes AF: 0.973 AC: 241645 AN: 248256 Hom.: 117639 AF XY: 0.974 AC XY: 130729 AN XY: 134168

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.954

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.988

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.972

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.974 AC: 1315992 AN: 1351142 Hom.: 640992 Cov.: 19 AF XY: 0.974 AC XY: 660815 AN XY: 678160

Gnomad4 AFR exome AF: 0.913

Gnomad4 AMR exome AF: 0.981

Gnomad4 ASJ exome AF: 0.954

Gnomad4 EAS exome AF: 0.987

Gnomad4 SAS exome AF: 0.988

Gnomad4 FIN exome AF: 0.979

Gnomad4 NFE exome AF: 0.974

Gnomad4 OTH exome AF: 0.971

GnomAD4 genome AF: 0.956 AC: 145628 AN: 152278 Hom.: 69693 Cov.: 32 AF XY: 0.958 AC XY: 71307 AN XY: 74458

Gnomad4 AFR AF: 0.910

Gnomad4 AMR AF: 0.971

Gnomad4 ASJ AF: 0.953

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.991

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.973

Gnomad4 OTH AF: 0.951

Alfa AF: 0.967 Hom.: 71295

Bravo AF: 0.953

Asia WGS AF: 0.986 AC: 3430 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Paragangliomas 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Mitochondrial complex 2 deficiency, nuclear type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Gastrointestinal stromal tumor Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.65

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: rs1022580; hg19: chr1-17359676;