rs1557045066

chrX-153693368-T-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_005629.4(SLC6A8):c.1016+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 splice_donor
• Scores: Splicing: ADA: 0.9897
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 5.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.743
• PP5: Variant X-153693368-T-C is Pathogenic according to our data. Variant chrX-153693368-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 520792.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-153693368-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1016+2T>C		splice_donor_variant		ENST00000253122.10
SLC6A8	NM_001142805.2	c.1016+2T>C		splice_donor_variant
SLC6A8	NM_001142806.1	c.671+2T>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1016+2T>C		splice_donor_variant		1	NM_005629.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Pathogenic:3 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	-	Variant interpreted as Pathogenic and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Feb 23, 2023	The NM_005629.4:c.1016+2T>C variant occurs within the canonical splice donor of intron 6 of SLC6A8. It is predicted to cause skipping of biologically-relevant-exon 6/13, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two male patients have been reported who are hemizygous for the variant (presumed to be different cases). One of these patients has profound intellectual disability, seizures, and elevated urine creatine/creatinine ratio (PMID 16738945) (PP4). There was "clinical suspicion" for a CCDS for the other patient., but results of follow up biochemical testing or brain magnetic resonance spectrscopy are not available (PMID 23660394). There is a ClinVar entry for this variant (Variation ID: 520792). 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 CCDS VCEP (Specifications Verions 1.1.0): PVS1, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 23, 2023). -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 09, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with SLC6A8-related conditions (PMID: 16738945, Invitae). ClinVar contains an entry for this variant (Variation ID: 520792). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 of the SLC6A8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC6A8 are known to be pathogenic (PMID: 22281021). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.40		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557045066; hg19: chrX-152958823;