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:c.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID:31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). 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. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC6A8 | ENST00000253122.10 | c.92C>T | p.Pro31Leu | missense_variant | 1/13 | 1 | NM_005629.4 | ENSP00000253122.5 | ||
PNCK | ENST00000458354.5 | c.-3+149G>A | intron_variant | 3 | ENSP00000401542.1 | |||||
PNCK | ENST00000480693.1 | n.64+149G>A | intron_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 | clinical testing | Revvity Omics, Revvity | May 23, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Nov 08, 2024 | The NM_005629.4:c.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID: 31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). 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. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) - |
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