NM_005629.4:c.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT

Variant names:

• chrX-153688627-AGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCG-CCGTGT
• rs1557043770
• NM_005629.4:c.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.53_137delinsCCGTGT (p.Lys18fs) variant in SLC6A8 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/13, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in population databases (PM2_Supporting), and to our current knowledge has not been reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:533702). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA658799891/MONDO:0010305/027

• Frequency: Genomes: not found (cov: 20)
• Consequence: SLC6A8 NM_005629.4 frameshift, missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.03
• 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]

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.

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.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT	p.Lys18ThrfsTer53	frameshift missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT	p.Lys18ThrfsTer53	frameshift missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT	p.Lys18ThrfsTer53	frameshift missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT	p.Lys18ThrfsTer53	frameshift missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.53_137delAGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCGinsCCGTGT	p.Lys18ThrfsTer53	frameshift missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 20

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Creatine transporter deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0

Splicing

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

Other links and lift over

dbSNP: rs1557043770; hg19: chrX-152954082;