rs782560726

Variant names:

• chrX-153695084-A-G
• rs782560726
• NM_005629.4:c.1778A>G
• SLC6A8 p.His593Arg

Your query was ambiguous. Multiple possible variants found:

• chrX-153695084-A-G
• chrX-153695084-A-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS1 BS2 BP4

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:
  • Genomes: 𝑓 0.00028 (2 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000027 (1 hom. 6 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.15
• Publications: 1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Orphanet

ACMG classification

Specifications for SLC6A8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1778A>G	p.His593Arg	missense	Exon 13 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1748A>G	p.His583Arg	missense	Exon 13 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1433A>G	p.His478Arg	missense	Exon 13 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.1778A>G	p.His593Arg	missense	Exon 13 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1775A>G	p.His592Arg	missense	Exon 13 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1769A>G	p.His590Arg	missense	Exon 13 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 29 AN: 112504 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000560

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00464

GnomAD2 exomes AF: 0.0000306 AC: 5 AN: 163260 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000487

GnomAD4 exome AF: 0.0000266 AC: 29 AN: 1089595 Hom.: 1 Cov.: 31 AF XY: 0.0000168 AC XY: 6 AN XY: 356981

African (AFR) AF: 0.00 AC: 0 AN: 26256

American (AMR) AF: 0.00 AC: 0 AN: 34490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19194

East Asian (EAS) AF: 0.000134 AC: 4 AN: 29896

South Asian (SAS) AF: 0.00 AC: 0 AN: 52717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3874

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 837900

Other (OTH) AF: 0.000482 AC: 22 AN: 45686

GnomAD4 genome AF: 0.000284 AC: 32 AN: 112558 Hom.: 2 Cov.: 23 AF XY: 0.0000288 AC XY: 1 AN XY: 34746

African (AFR) AF: 0.00 AC: 0 AN: 31017

American (AMR) AF: 0.00186 AC: 20 AN: 10748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.000562 AC: 2 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6241

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53164

Other (OTH) AF: 0.00655 AC: 10 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Creatine transporter deficiency (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.082	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.13
Sift	Benign	0.37	T
Sift4G	Benign	0.36	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.78
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs782560726;

hg19: chrX-152960539;