rs34916635
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1PM5BP4_StrongBP6_Very_Strong
The NM_003000.3(SDHB):c.158G>A(p.Gly53Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000284 in 1,614,034 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G53R) has been classified as Uncertain significance.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.158G>A | p.Gly53Glu | missense_variant | 2/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.158G>A | p.Gly53Glu | missense_variant | 2/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.158G>A | p.Gly53Glu | missense_variant | 2/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152190Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000533 AC: 134AN: 251378Hom.: 1 AF XY: 0.000523 AC XY: 71AN XY: 135876
GnomAD4 exome AF: 0.000272 AC: 397AN: 1461844Hom.: 2 Cov.: 32 AF XY: 0.000268 AC XY: 195AN XY: 727234
GnomAD4 genome ? AF: 0.000401 AC: 61AN: 152190Hom.: 1 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74342
ClinVar
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 08, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | SDHB: BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 08, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2020 | This variant is associated with the following publications: (PMID: 23512077, 25694510, 21979946, 25394176, 19802898, 18458953, 23072324, 20923864, 28873162, 30152102) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 17, 2021 | Variant summary: SDHB c.158G>A (p.Gly53Glu) results in a non-conservative amino acid change located in the 2Fe-2S ferredoxin-type iron-sulfur binding domain (IPR010141) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251378 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (2.2e-07), strongly suggesting that the variant is benign. Although, this variant has been reported in the literature (example, Fishbein_2013, Cox_2018), to our knowledge, no occurrence of c.158G>A in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2015 | This alteration is classified as 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 15, 2021 | - - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Paragangliomas 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 20, 2022 | - - |
SDHB-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 13, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary pheochromocytoma-paraganglioma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 21, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Carney-Stratakis syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 21, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4;CN072330:Cowden syndrome 1 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at