chrX-153695084-A-G
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS1BS2BP4
This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1778A>G variant in SLC6A8 is a missense variant predicted to cause the substitution of a histidine by an arginine at amino acid position 593 (p.His593Arg). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency is 0.0004421 (20/45238 alleles; 2 homozygotes, 0 hemizygotes) in the Admixed American population. This MAF is higher than the ClinGen CCDS VCEP's threshold for BS1 (>0.0002), meeting this criterion (BS1). Overall, across all populations, there are 3 homozygotes and 7 hemizygotes in gnomAD v4.1.0. (BS2). The computational predictor REVEL gives a score of 0.133 suggesting that the variant has no impact on protein function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465144). In summary, this variant meets criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549662/MONDO:0010305/027
Frequency
Consequence
NM_005629.4 missense
Scores
Clinical Significance
Conservation
Publications
- creatine transporter deficiencyInheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC6A8 | NM_005629.4 | c.1778A>G | p.His593Arg | missense_variant | Exon 13 of 13 | ENST00000253122.10 | NP_005620.1 | |
SLC6A8 | NM_001142805.2 | c.1748A>G | p.His583Arg | missense_variant | Exon 13 of 13 | NP_001136277.1 | ||
SLC6A8 | NM_001142806.1 | c.1433A>G | p.His478Arg | missense_variant | Exon 13 of 13 | NP_001136278.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC6A8 | ENST00000253122.10 | c.1778A>G | p.His593Arg | missense_variant | Exon 13 of 13 | 1 | NM_005629.4 | ENSP00000253122.5 | ||
SLC6A8 | ENST00000430077.6 | c.1433A>G | p.His478Arg | missense_variant | Exon 13 of 13 | 2 | ENSP00000403041.2 | |||
SLC6A8 | ENST00000485324.1 | n.2085A>G | non_coding_transcript_exon_variant | Exon 6 of 6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000258 AC: 29AN: 112504Hom.: 2 Cov.: 23 show subpopulations
GnomAD2 exomes AF: 0.0000306 AC: 5AN: 163260 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.0000266 AC: 29AN: 1089595Hom.: 1 Cov.: 31 AF XY: 0.0000168 AC XY: 6AN XY: 356981 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000284 AC: 32AN: 112558Hom.: 2 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34746 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Creatine transporter deficiency Uncertain:1Benign:1
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SLC6A8-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at