NM_005629.4:c.1714G>A

Variant names:

• chrX-153694836-G-A
• rs2872524
• NM_005629.4:c.1714G>A

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.1714G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 572 (p.Val572Met). 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 0.0000369 (33/894244 alleles, 12 hemizygotes) in the European (Non-Finnish) population. This MAF 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. There are 14 hemizygotes in gnomAD v4.1.0. (12 in the European non-Finnish, one in the "other" and one in the S. Asian population) (BS2). The computational predictor REVEL gives a score of 0.689, 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: 449188). Due to the presence of 14 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 ACMG/AMP 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/CA10549625/MONDO:0010305/027

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000039 (0 hom. 14 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 3.25
• 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1714G>A	p.Val572Met	missense	Exon 12 of 13	NP_005620.1
	SLC6A8	NM_001142805.2		c.1684G>A	p.Val562Met	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1369G>A	p.Val457Met	missense	Exon 12 of 13	NP_001136278.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1714G>A	p.Val572Met	missense	Exon 12 of 13	ENSP00000253122.5
	SLC6A8	ENST00000430077.6	TSL:2	c.1369G>A	p.Val457Met	missense	Exon 12 of 13	ENSP00000403041.2
	SLC6A8	ENST00000485324.1	TSL:2	n.2021G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000397 AC: 7 AN: 176255 AF XY: 0.0000481

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000644

Gnomad NFE exome AF: 0.0000772

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 43 AN: 1094605 Hom.: 0 Cov.: 38 AF XY: 0.0000388 AC XY: 14 AN XY: 360917

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 35024

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30170

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53702

European-Finnish (FIN) AF: 0.000125 AC: 5 AN: 39983

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3371

European-Non Finnish (NFE) AF: 0.0000393 AC: 33 AN: 840748

Other (OTH) AF: 0.0000653 AC: 3 AN: 45917

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000907 AC: 11

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Creatine transporter deficiency (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.40
MVP		0.92
MPC		0.61
ClinPred		0.40	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.79
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs2872524; hg19: chrX-152960291;