rs146399542

chr1-17053987-G-Achr1-17053987-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_003000.3(SDHB):c.33C>T(p.Arg11=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHB NM_003000.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.675

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-17053987-G-A is Benign according to our data. Variant chr1-17053987-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 528753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.675 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.33C>T	p.Arg11=	synonymous_variant	1/8	ENST00000375499.8
SDHB	NM_001407361.1	c.33C>T	p.Arg11=	synonymous_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.33C>T	p.Arg11=	synonymous_variant	1/8	1	NM_003000.3	P1
SDHB	ENST00000466613.2	n.45C>T		non_coding_transcript_exon_variant	1/3	2
SDHB	ENST00000485515.5	n.21C>T		non_coding_transcript_exon_variant	1/7	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 242918 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132354

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460680 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2020

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary pheochromocytoma-paraganglioma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.2
Dann	Benign	0.74
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7

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: rs146399542; hg19: chr1-17380482;