1-17053996-G-A

Variant names:

• chr1-17053996-G-A
• rs148738139
• NM_003000.3:c.24C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003000.3(SDHB):​c.24C>T​(p.Ser8Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00554 in 1,612,708 control chromosomes in the GnomAD database, including 31 homozygotes. 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. S8S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (29 hom.)
• Consequence: SDHB NM_003000.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 3.70

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-17053996-G-A is Benign according to our data. Variant chr1-17053996-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17053996-G-A is described in Lovd as [Benign]. Variant chr1-17053996-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00437 (665/152316) while in subpopulation NFE AF = 0.00657 (447/68032). AF 95% confidence interval is 0.00607. There are 2 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.24C>T	p.Ser8Ser	synonymous_variant	Exon 1 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.24C>T	p.Ser8Ser	synonymous_variant	Exon 1 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.24C>T	p.Ser8Ser	synonymous_variant	Exon 1 of 8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000466613.2	n.36C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
SDHB	ENST00000485515.5	n.12C>T		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000519322.1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152198 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00430 AC: 1043 AN: 242730 AF XY: 0.00418

Gnomad AFR exome AF: 0.000980

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00566 AC: 8269 AN: 1460392 Hom.: 29 Cov.: 30 AF XY: 0.00552 AC XY: 4012 AN XY: 726450

Gnomad4 AFR exome AF: 0.000747 AC: 25 AN: 33448

Gnomad4 AMR exome AF: 0.000358 AC: 16 AN: 44646

Gnomad4 ASJ exome AF: 0.00199 AC: 52 AN: 26084

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39662

Gnomad4 SAS exome AF: 0.0000349 AC: 3 AN: 86050

Gnomad4 FIN exome AF: 0.0144 AC: 761 AN: 53024

Gnomad4 NFE exome AF: 0.00646 AC: 7176 AN: 1111504

Gnomad4 Remaining exome AF: 0.00392 AC: 236 AN: 60244

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152316 Hom.: 2 Cov.: 31 AF XY: 0.00415 AC XY: 309 AN XY: 74466

Gnomad4 AFR AF: 0.000986 AC: 0.000986098 AN: 0.000986098

Gnomad4 AMR AF: 0.00124 AC: 0.00124118 AN: 0.00124118

Gnomad4 ASJ AF: 0.00144 AC: 0.00144009 AN: 0.00144009

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0139 AC: 0.0139386 AN: 0.0139386

Gnomad4 NFE AF: 0.00657 AC: 0.00657044 AN: 0.00657044

Gnomad4 OTH AF: 0.000946 AC: 0.000946074 AN: 0.000946074

Alfa AF: 0.00491 Hom.: 2

Bravo AF: 0.00337

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00487

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Feb 15, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:7

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHB: BP4, BS2 -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paragangliomas 4 Benign:2

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary pheochromocytoma-paraganglioma Benign:2

Sep 20, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Benign:1

Aug 10, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Aug 03, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Carney-Stratakis syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs148738139; hg19: chr1-17380491; COSMIC: COSV64965451;