1-17027878-GGAAGAAGAAGAA-GGAAGAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_003000.3(SDHB):c.424-19_424-14delTTCTTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,377,784 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 11 hom. )

Consequence

SDHB
NM_003000.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 2.43

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: Ambry Genetics, Genomics England PanelApp, 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: Benign. The variant received -9 ACMG points.

BP6

Variant 1-17027878-GGAAGAA-G is Benign according to our data. Variant chr1-17027878-GGAAGAA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258890.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00222 (337/151668) while in subpopulation AMR AF = 0.00382 (58/15188). AF 95% confidence interval is 0.00303. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.424-19_424-14delTTCTTC		intron	N/A	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.370-19_370-14delTTCTTC		intron	N/A	NP_001394290.1	A0AAQ5BHD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SDHB	ENST00000375499.8	TSL:1 MANE Select	c.424-19_424-14delTTCTTC	intron	N/A	ENSP00000364649.3	P21912
SDHB	ENST00000714034.1		c.469-19_469-14delTTCTTC	intron	N/A	ENSP00000519325.1	A0AAQ5BHC9
SDHB	ENST00000925621.1		c.418-19_418-14delTTCTTC	intron	N/A	ENSP00000595680.1

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

337

AN:

151552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00382

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.000574

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00224

AC:

500

AN:

222768

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.000978

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.00433

Gnomad EAS exome

AF:

0.000440

Gnomad FIN exome

AF:

0.000444

Gnomad NFE exome

AF:

0.00301

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.00229

AC:

2813

AN:

1226116

Hom.:

AF XY:

0.00238

AC XY:

1483

AN XY:

622084

show subpopulations

African (AFR)

AF:

0.000795

AC:

AN:

28926

American (AMR)

AF:

0.00162

AC:

AN:

44354

Ashkenazi Jewish (ASJ)

AF:

0.00488

AC:

120

AN:

24572

East Asian (EAS)

AF:

0.000155

AC:

AN:

38586

South Asian (SAS)

AF:

0.00229

AC:

186

AN:

81242

European-Finnish (FIN)

AF:

0.000538

AC:

AN:

52074

Middle Eastern (MID)

AF:

0.00209

AC:

AN:

5264

European-Non Finnish (NFE)

AF:

0.00245

AC:

2197

AN:

898562

Other (OTH)

AF:

0.00324

AC:

170

AN:

52536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

140

280

420

560

700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00222

AC:

337

AN:

151668

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

160

AN XY:

74086

show subpopulations

African (AFR)

AF:

0.000556

AC:

AN:

41360

American (AMR)

AF:

0.00382

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.00146

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000574

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00309

AC:

210

AN:

67918

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00128

Hom.:

Bravo

AF:

0.00232

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Carney-Stratakis syndrome (1)

Cowden syndrome (1)

Hereditary pheochromocytoma and paraganglioma (1)

Pheochromocytoma (1)

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over