chrX-153694723-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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]

SLC6A8 Gene-Disease associations (from GenCC):

• creatine transporter deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1601T>C	p.Ile534Thr	missense	Exon 12 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1571T>C	p.Ile524Thr	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1256T>C	p.Ile419Thr	missense	Exon 12 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1601T>C	p.Ile534Thr	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1598T>C	p.Ile533Thr	missense	Exon 12 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1592T>C	p.Ile531Thr	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

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

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

African (AFR) AF: 0.00 AC: 0 AN: 26365

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40369

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3486

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841861

Other (OTH) AF: 0.0000217 AC: 1 AN: 46008

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

African (AFR) AF: 0.00 AC: 0 AN: 30904

American (AMR) AF: 0.00 AC: 0 AN: 10731

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2751

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53075

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Creatine transporter deficiency (3)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.78	T
Sift4G	Benign	0.69	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
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs797045971; hg19: chrX-152960178;