X-153688666-C-T
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4
This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.92C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 31 (p.Pro31Leu). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0001300 (4/30763 alleles) in the European population with 1 hemizygote, which is >0.0002 and >1 hemizygote, therefore PM2_Supporting criteria is not applicable. The computational predictor REVEL gives a score of 0.114 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing. This variant has been reported in a single individual in the literature (PMID:31222513) in a proband (case 1) with seizures, neurological regression, and spasticity who was found by WES to be hemizygous for the c.92C>T (p.Pro31Leu) variant, however biochemical studies were not performed to confirm creatine transporter deficiency, therefore this proband cannot be used as evidence for SLC6A8 variant classification. There is a ClinVar entry for this variant (Variation ID:572616). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA415076214/MONDO:0010305/027
Frequency
Consequence
NM_005629.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC6A8 | NM_005629.4 | c.92C>T | p.Pro31Leu | missense_variant | 1/13 | ENST00000253122.10 | |
SLC6A8 | NM_001142805.2 | c.92C>T | p.Pro31Leu | missense_variant | 1/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC6A8 | ENST00000253122.10 | c.92C>T | p.Pro31Leu | missense_variant | 1/13 | 1 | NM_005629.4 | P1 | |
PNCK | ENST00000458354.5 | c.-3+149G>A | intron_variant | 3 | |||||
PNCK | ENST00000480693.1 | n.64+149G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000832 AC: 9AN: 108178Hom.: 1 Cov.: 21 AF XY: 0.000127 AC XY: 4AN XY: 31496
GnomAD3 exomes AF: 0.0000329 AC: 2AN: 60779Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 19963
GnomAD4 exome AF: 0.0000382 AC: 37AN: 969021Hom.: 0 Cov.: 26 AF XY: 0.0000422 AC XY: 13AN XY: 307803
GnomAD4 genome AF: 0.0000647 AC: 7AN: 108195Hom.: 0 Cov.: 21 AF XY: 0.000127 AC XY: 4AN XY: 31521
ClinVar
Submissions by phenotype
Creatine transporter deficiency Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 23, 2023 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Jun 06, 2022 | The NM_005629.4(SLC6A8):c.92C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 31 (p.Pro31Leu). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0001300 (4/30763 alleles) in the European population with 1 hemizygote, which is >0.0002 and >1 hemizygote, therefore PM2_Supporting criteria is not applicable. The computational predictor REVEL gives a score of 0.114 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing. This variant has been reported in a single individual in the literature (PMID:31222513) in a proband (case 1) with seizures, neurological regression, and spasticity who was found by WES to be hemizygous for the c.92C>T (p.Pro31Leu) variant, however biochemical studies were not performed to confirm creatine transporter deficiency, therefore this proband cannot be used as evidence for SLC6A8 variant classification. There is a ClinVar entry for this variant (Variation ID:572616). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2021 | This variant is associated with the following publications: (PMID: 31222513) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at