X-153688627-AGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCG-CCGTGT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005629.4(SLC6A8):c.53_137delinsCCGTGT(p.Lys18ThrfsTer53) variant causes a frameshift change. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K18K) has been classified as Likely benign.

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

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

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 101 pathogenic variants in the truncated region.
• PP5: Variant X-153688627-AGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCG-CCGTGT is Pathogenic according to our data. Variant chrX-153688627-AGAAGGGCCCCCTCATCGCGCCCGGGCCCGACGGGGCCCCGGCCAAGGGCGACGGCCCCGTGGGCCTGGGGACACCCGGCGGCCG-CCGTGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 533702.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.53_137delinsCCGTGT	p.Lys18ThrfsTer53	frameshift_variant	1/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.53_137delinsCCGTGT	p.Lys18ThrfsTer53	frameshift_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.53_137delinsCCGTGT	p.Lys18ThrfsTer53	frameshift_variant	1/13	1	NM_005629.4	P1
PNCK	ENST00000458354.5	c.-3+104_-3+188delinsACACGG		intron_variant		3
PNCK	ENST00000480693.1	n.64+104_64+188delinsACACGG		intron_variant, non_coding_transcript_variant		5
SLC6A8	ENST00000476466.1			upstream_gene_variant		3

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2018	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021). This variant has not been reported in the literature in individuals with SLC6A8-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Lys18Thrfs*53) in the SLC6A8 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557043770; hg19: chrX-152954082;