rs1022612492
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_002693.3(POLG):c.167C>T(p.Pro56Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. P56R) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.167C>T | p.Pro56Leu | missense_variant | 2/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.222C>T | p.Ala74= | synonymous_variant | 2/23 | ||
POLG | NM_001126131.2 | c.167C>T | p.Pro56Leu | missense_variant | 2/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.167C>T | p.Pro56Leu | missense_variant | 2/23 | 1 | NM_002693.3 | P1 | |
POLGARF | ENST00000706918.1 | c.222C>T | p.Ala74= | synonymous_variant | 1/2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1453840Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2AN XY: 723488
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 56 of the POLG protein (p.Pro56Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLG-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at