rs797045971

Variant names:

• chrX-153694723-T-C
• rs797045971
• NM_005629.4:c.1601T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1601T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of an isoleucine by a threonine at amino acid position 534 (p.Ile534Thr). 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 (MAF) is 0.00001229 (11/894936 alleles, 6 hemizygotes) in the European (Non-Finnish) population. While this MAF is below the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), PM2_Supporting cannot be applied due to the presence of hemizygotes. Overall, there are 7 hemizygotes in gnomAD v4.1.0 (6 in the European non-Finnish population and one in the remaining population) (BS2). The computational predictor REVEL gives a score of 0.474, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 212211). Due to the presence of 7 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2 (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA205226/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.0000082 (0 hom. 7 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2 O:1
• Conservation: PhyloP100: 2.71

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1601T>C	p.Ile534Thr	missense_variant	Exon 12 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1571T>C	p.Ile524Thr	missense_variant	Exon 12 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1256T>C	p.Ile419Thr	missense_variant	Exon 12 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1601T>C	p.Ile534Thr	missense_variant	Exon 12 of 13	1	NM_005629.4	ENSP00000253122.5
SLC6A8	ENST00000430077.6	c.1256T>C	p.Ile419Thr	missense_variant	Exon 12 of 13	2		ENSP00000403041.2
SLC6A8	ENST00000485324.1	n.1908T>C		non_coding_transcript_exon_variant	Exon 5 of 6	2
SLC6A8	ENST00000413787.1	c.*147T>C		downstream_gene_variant		5		ENSP00000400463.1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112224 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34414

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000820 AC: 9 AN: 1096970 Hom.: 0 Cov.: 37 AF XY: 0.0000193 AC XY: 7 AN XY: 362872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000950

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112224 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000565

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Uncertain:1 Benign:1 Other:1

Mar 13, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_005629.4:c.1601T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of an isoleucine by a threonine at amino acid position 534 (p.Ile534Thr). 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 (MAF) is 0.00001229 (11/894936 alleles, 6 hemizygotes) in the European (Non-Finnish) population. While this MAF is below the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002), PM2_Supporting cannot be applied due to the presence of hemizygotes. Overall, there are 7 hemizygotes in gnomAD v4.1.0 (6 in the European non-Finnish population and one in the remaining population) (BS2). The computational predictor REVEL gives a score of 0.474, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 212211). Due to the presence of 7 hemizygotes in gnomAD v4.1.0, the consensus of the CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2 (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025) -

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 534 of the SLC6A8 protein (p.Ile534Thr). This variant is present in population databases (rs797045971, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. ClinVar contains an entry for this variant (Variation ID: 212211). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC6A8 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Uncertain:1

Feb 13, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not specified Benign:1

Jun 08, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Benign	0.17
DEOGEN2	Benign	0.19	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.78	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.37	B;.
Vest4		0.80
MutPred		0.57		Loss of stability (P = 0.0185);.;
MVP		0.96
MPC		0.53
ClinPred		0.47	T
GERP RS		4.8
Varity_R		0.45
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045971; hg19: chrX-152960178;