1-17027878-GGAAGAAGAAGAA-GGAAGAAGAAGAAGAA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1

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:10

Conservation

PhyloP100: 0.00
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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 id is 44644.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=5, Uncertain_significance=3}.
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHBNM_003000.3 linkc.424-16_424-14dupTTC intron_variant Intron 4 of 7 ENST00000375499.8 NP_002991.2 P21912
SDHBNM_001407361.1 linkc.370-16_370-14dupTTC intron_variant Intron 4 of 7 NP_001394290.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHBENST00000375499.8 linkc.424-14_424-13insTTC intron_variant Intron 4 of 7 1 NM_003000.3 ENSP00000364649.3 P21912

Frequencies

GnomAD3 genomes
AF:
0.00118
AC:
179
AN:
151550
Hom.:
1
Cov.:
32
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
GnomAD3 exomes
AF:
0.00127
AC:
284
AN:
222768
Hom.:
0
AF XY:
0.00128
AC XY:
154
AN XY:
120738
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 SAS exome
AF:
0.00205
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.:
0
Cov.:
16
AF XY:
0.000804
AC XY:
500
AN XY:
622142
show subpopulations
Gnomad4 AFR exome
AF:
0.000519
Gnomad4 AMR exome
AF:
0.00158
Gnomad4 ASJ exome
AF:
0.000203
Gnomad4 EAS exome
AF:
0.000207
Gnomad4 SAS exome
AF:
0.00166
Gnomad4 FIN exome
AF:
0.000211
Gnomad4 NFE exome
AF:
0.000688
Gnomad4 OTH exome
AF:
0.000913
GnomAD4 genome
AF:
0.00119
AC:
180
AN:
151666
Hom.:
1
Cov.:
32
AF XY:
0.00105
AC XY:
78
AN XY:
74084
show subpopulations
Gnomad4 AFR
AF:
0.000725
Gnomad4 AMR
AF:
0.00112
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000388
Gnomad4 SAS
AF:
0.00250
Gnomad4 FIN
AF:
0.000191
Gnomad4 NFE
AF:
0.00146
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:10
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

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 -

Feb 03, 2023
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Mar 01, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary pheochromocytoma-paraganglioma Benign:2
Sep 21, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 05, 2024
All of Us Research Program, National Institutes of 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;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
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 v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34261028; hg19: chr1-17354373; API