rs1557045066

Variant names:

• chrX-153693368-T-C
• rs1557045066
• NM_005629.4:c.1016+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA415085022/MONDO:0010305/027

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

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

Our verdict: Pathogenic. The variant received 10 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.
• 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.1016+2T>C		splice_donor intron	N/A	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1016+2T>C		splice_donor intron	N/A	NP_001136277.1
	SLC6A8	NM_001142806.1		c.671+2T>C		splice_donor intron	N/A	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.1016+2T>C		splice_donor intron	N/A	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1016+2T>C		splice_donor intron	N/A	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1016+2T>C		splice_donor intron	N/A	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Creatine transporter deficiency (4)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.0
GERP RS		5.0
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1557045066; hg19: chrX-152958823;