rs796052895
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_002693.3(POLG):āc.86C>Gā(p.Ser29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,407,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S29P) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.86C>G | p.Ser29Cys | missense_variant | 2/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.141C>G | p.Leu47= | synonymous_variant | 2/23 | ||
POLG | NM_001126131.2 | c.86C>G | p.Ser29Cys | missense_variant | 2/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.86C>G | p.Ser29Cys | missense_variant | 2/23 | 1 | NM_002693.3 | P1 | |
POLGARF | ENST00000706918.1 | c.141C>G | p.Leu47= | synonymous_variant | 1/2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000128 AC: 2AN: 156754Hom.: 0 AF XY: 0.0000116 AC XY: 1AN XY: 86482
GnomAD4 exome AF: 0.00000497 AC: 7AN: 1407236Hom.: 0 Cov.: 32 AF XY: 0.00000718 AC XY: 5AN XY: 696828
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2013 | p.Ser29Cys (TCC>TGC): c.86 C>G in exon 2 of the POLG gene (NM_002693.2). The Ser29Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Ser29Cys is a semi-conservative amino acid substitution as both Serine and Cysteine are uncharged, polar residues; however, the introduction of a Cysteine residue, which impacts disulfide bonding, may affect the secondary structure of the POLG protein. It alters a conserved position in the protein; however, disease-causing missense mutations have not been reported at nearby residues. In silico algorithms are not consistent in their predictions of whether or not Ser29Cys is damaging to the structure/function of the POLG protein. Therefore, based on the currently available information, it is unclear whether Ser29Cys is a disease-causing mutation or a rare benign variant.The variant is found in MITO24,INFANT-EPI panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 27, 2018 | - - |
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 10, 2022 | - - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 07, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 29 of the POLG protein (p.Ser29Cys). This variant is present in population databases (rs796052895, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206550). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at