rs1060502808
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005629.4(SLC6A8):c.974_975del(p.Thr325SerfsTer139) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 24)
Consequence
SLC6A8
NM_005629.4 frameshift
NM_005629.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.98
Genes affected
SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-153693321-TCA-T is Pathogenic according to our data. Variant chrX-153693321-TCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 410218.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-153693321-TCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC6A8 | NM_005629.4 | c.974_975del | p.Thr325SerfsTer139 | frameshift_variant | 6/13 | ENST00000253122.10 | |
SLC6A8 | NM_001142805.2 | c.974_975del | p.Thr325SerfsTer129 | frameshift_variant | 6/13 | ||
SLC6A8 | NM_001142806.1 | c.629_630del | p.Thr210SerfsTer139 | frameshift_variant | 6/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC6A8 | ENST00000253122.10 | c.974_975del | p.Thr325SerfsTer139 | frameshift_variant | 6/13 | 1 | NM_005629.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Creatine transporter deficiency Pathogenic:3
Pathogenic, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | May 02, 2024 | The NM_005629.4:c.972_973del (p.Thr325SerfsTer139) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of 13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two maternal half-brothers have been reported to be hemizygous for the variant, both with clinical features consistent with creatine transporter deficiency, markedly reduced creatine level on brain MRS, elevated urine creatine/creatinine ratio, and <3% transporter activity in fibroblasts (PMID 20602486) (PP4_Strong). This variant is not in gnomAD v2.1.1. or v4.1.0 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 410218). In summary, this variant meets the criteria to be classified as pathogenic for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on May 2, 2024) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 04, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 18, 2022 | This sequence change creates a premature translational stop signal (p.Thr325Serfs*139) in the SLC6A8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked cerebral creatine deficiency (PMID: 20602486). ClinVar contains an entry for this variant (Variation ID: 410218). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
BranchPoint Hunter
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Splicing
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Calibrated prediction
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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