1-17027878-GGAAGAAGAAGAA-GGAAGAAGAAGAAGAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_003000.3(SDHB):c.424-16_424-14dupTTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0008 in 1,377,890 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

SDHB
NM_003000.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:11

Conservation

PhyloP100: 0.00

Publications

0 publications found

Variant links:

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]

SDHB Gene-Disease associations (from GenCC):

Carney-Stratakis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
gastrointestinal stromal tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
pheochromocytoma/paraganglioma syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
renal cell carcinoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
mitochondrial complex 2 deficiency, nuclear type 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex II deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SDHB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 1-17027878-G-GGAA is Benign according to our data. Variant chr1-17027878-G-GGAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44644.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00119 (180/151666) while in subpopulation SAS AF = 0.0025 (12/4804). AF 95% confidence interval is 0.00144. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.424-16_424-14dupTTC		intron	N/A	NP_002991.2
	SDHB	NM_001407361.1		c.370-16_370-14dupTTC		intron	N/A	NP_001394290.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SDHB	ENST00000375499.8	TSL:1 MANE Select	c.424-14_424-13insTTC	intron	N/A	ENSP00000364649.3
SDHB	ENST00000714034.1		c.469-14_469-13insTTC	intron	N/A	ENSP00000519325.1
SDHB	ENST00000491274.6	TSL:5	c.382-14_382-13insTTC	intron	N/A	ENSP00000480482.2

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

151550

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000727

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00127

AC:

284

AN:

222768

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.000838

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.000317

Gnomad EAS exome

AF:

0.000503

Gnomad FIN exome

AF:

0.000111

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.000752

AC:

922

AN:

1226224

Hom.:

Cov.:

AF XY:

0.000804

AC XY:

500

AN XY:

622142

show subpopulations

African (AFR)

AF:

0.000519

AC:

AN:

28922

American (AMR)

AF:

0.00158

AC:

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.000203

AC:

AN:

24580

East Asian (EAS)

AF:

0.000207

AC:

AN:

38586

South Asian (SAS)

AF:

0.00166

AC:

135

AN:

81248

European-Finnish (FIN)

AF:

0.000211

AC:

AN:

52104

Middle Eastern (MID)

AF:

0.00228

AC:

AN:

5264

European-Non Finnish (NFE)

AF:

0.000688

AC:

618

AN:

898622

Other (OTH)

AF:

0.000913

AC:

AN:

52548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00119

AC:

180

AN:

151666

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74084

show subpopulations

African (AFR)

AF:

0.000725

AC:

AN:

41360

American (AMR)

AF:

0.00112

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.00250

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Dec 06, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The 424-16_424-14du pTTC variant in SDHB has not been previously identified by our laboratory or in the literature. This variant is located in the 3' splice region. Computational t ools do not suggest an impact to splicing. However, this information is not pred ictive enough to rule out pathogenicity. In summary, although this data supports that the 424-16_424-14dupTTC variant may be benign, additional studies are need ed to fully assess its clinical significance.

PreventionGenetics, part of Exact Sciences

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

not provided

Benign:3

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SDHB: BP4, BS1

Mar 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Hereditary pheochromocytoma-paraganglioma

Benign:2

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pheochromocytoma

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Carney-Stratakis syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pheochromocytoma/paraganglioma syndrome 4

Benign:1

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 intronic and is not expected to impact mRNA splicing.

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 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

Nov 16, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Dec 14, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over