rs115561881

Positions:

• chr1-17022595-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003000.3(SDHB):​c.765+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,524 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (5 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.38

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=-0.82).
• BP6: Variant 1-17022595-C-T is Benign according to our data. Variant chr1-17022595-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17022595-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000171 (26/152304) while in subpopulation SAS AF= 0.00456 (22/4828). AF 95% confidence interval is 0.00308. There are 1 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.765+13G>A		intron_variant		ENST00000375499.8
SDHB	NM_001407361.1	c.711+13G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.765+13G>A		intron_variant		1	NM_003000.3	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000684 AC: 172 AN: 251342 Hom.: 2 AF XY: 0.000927 AC XY: 126 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00523

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000328 AC: 480 AN: 1461220 Hom.: 5 Cov.: 31 AF XY: 0.000481 AC XY: 350 AN XY: 726940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00467

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Oct 06, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs115561881; hg19: chr1-17349090;