11-61437782-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_017841.4(SDHAF2):c.194C>T(p.Thr65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T65S) has been classified as Likely benign.
Frequency
Consequence
NM_017841.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHAF2 | ENST00000301761.7 | c.194C>T | p.Thr65Ile | missense_variant | Exon 2 of 4 | 1 | NM_017841.4 | ENSP00000301761.3 | ||
ENSG00000256591 | ENST00000541135.5 | c.194C>T | p.Thr65Ile | missense_variant | Exon 2 of 5 | 4 | ENSP00000443130.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250796Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135608
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary pheochromocytoma-paraganglioma Uncertain:2
This missense variant replaces threonine with isoleucine at codon 65 of the SDHAF2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has been identified in 2/250796 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 65 of the SDHAF2 protein (p.Thr65Ile). This variant is present in population databases (rs752462796, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 576139). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Paragangliomas 2 Uncertain:1
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not provided Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.T65I variant (also known as c.194C>T), located in coding exon 2 of the SDHAF2 gene, results from a C to T substitution at nucleotide position 194. The threonine at codon 65 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at