rs143916832
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005629.4(SLC6A8):c.1494C>G(p.Tyr498Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y498Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005629.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC6A8 | NM_005629.4 | c.1494C>G | p.Tyr498Ter | stop_gained, splice_region_variant | 10/13 | ENST00000253122.10 | |
SLC6A8 | NM_001142805.2 | c.1464C>G | p.Tyr488Ter | stop_gained, splice_region_variant | 10/13 | ||
SLC6A8 | NM_001142806.1 | c.1149C>G | p.Tyr383Ter | stop_gained, splice_region_variant | 10/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC6A8 | ENST00000253122.10 | c.1494C>G | p.Tyr498Ter | stop_gained, splice_region_variant | 10/13 | 1 | NM_005629.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Creatine transporter deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | St George's Genomics Service, St George's University Hospitals NHS FT | Aug 20, 2018 | This variant was identified via whole exome and subsequently whole genome analysis of a family trio. In this family the variant has been shown to occur de novo and was not reported in any reviewed variant databases at the time of identification; however other pathogenic nonsense variants 3' to this variant have been reported. The consequence is predicted to be a truncated protein (stop gain) with loss of the 3' portion of the Sodium:neurotransmitter symporter, creatine (IPR002984) domain. Complete loss of a protein product or residual functionality of a truncated protein product has not been confirmed by further investigations. Variants in this X-linked gene have previously been associated with cerebral creatine deficiency syndrome (type 1) and matched phenotypically. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at