rs777580299
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7
The NM_152468.5(TMC8):c.2073G>A(p.Pro691=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,594,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
TMC8
NM_152468.5 synonymous
NM_152468.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.77
Genes affected
TMC8 (HGNC:20474): (transmembrane channel like 8) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 8 predicted transmembrane domains and 3 leucine zipper motifs. [provided by RefSeq, Jul 2008]
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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;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP7
Synonymous conserved (PhyloP=-2.78 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMC8 | NM_152468.5 | c.2073G>A | p.Pro691= | synonymous_variant | 16/16 | ENST00000318430.10 | NP_689681.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMC8 | ENST00000318430.10 | c.2073G>A | p.Pro691= | synonymous_variant | 16/16 | 1 | NM_152468.5 | ENSP00000325561 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000192 AC: 4AN: 208242Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 114736
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GnomAD4 exome AF: 0.0000187 AC: 27AN: 1442328Hom.: 0 Cov.: 31 AF XY: 0.0000209 AC XY: 15AN XY: 716256
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epidermodysplasia verruciformis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 21, 2018 | This sequence change affects codon 691 of the TMC8 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TMC8 protein. This variant is present in population databases (rs777580299, ExAC 0.02%). This variant has not been reported in the literature in individuals with TMC8-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at