rs122453113

Variant names:

• chrX-153694577-C-T
• rs122453113
• NM_005629.4:c.1540C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1_Strong PP1_Strong PP4_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1540C>T (p.Arg514Ter) variant in SLC6A8 is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant-exon 11/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). A male patient has been reported with almost complete absence of the creatine signal on brain MRS, elevated creatine in urine, and virtually undetectable creatine transport in fibroblasts (PMID:11326334) (PP4_Strong). The mother, maternal aunt, and maternal grandmother are all heterozygous for the variant and all have evidence of creatine transporter deficiency. The paternal uncle has severe intellectual disability but was unavailable for study (PMID:11326334) (PP1_Strong). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral creatine Deficiencies Variant Curation Expert Panel CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP1_Strong, PP4_Strong, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Oct. 13, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256009/MONDO:0010305/027

• Frequency: Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
• Consequence: SLC6A8 NM_005629.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 1.64
• Publications: 6 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

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1540C>T	p.Arg514*	stop_gained	Exon 11 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1510C>T	p.Arg504*	stop_gained	Exon 11 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1195C>T	p.Arg399*	stop_gained	Exon 11 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.1540C>T	p.Arg514*	stop_gained	Exon 11 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1537C>T	p.Arg513*	stop_gained	Exon 11 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1531C>T	p.Arg511*	stop_gained	Exon 11 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109403 Hom.: 0 Cov.: 22

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: 0.00420

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109446 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31822

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29962

American (AMR) AF: 0.00 AC: 0 AN: 10435

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3436

South Asian (SAS) AF: 0.00 AC: 0 AN: 2504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5744

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52349

Other (OTH) AF: 0.00 AC: 0 AN: 1497

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Creatine transporter deficiency (3)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		1.6
Vest4		0.93
GERP RS		4.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs122453113; hg19: chrX-152960032;