rs80338739

Variant names:

• chrX-153690427-TTTC-T
• rs80338739
• NM_005629.4:c.321_323delCTT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM4_Supporting PP5_Very_Strong

The NM_005629.4(SLC6A8):​c.321_323delCTT​(p.Phe107del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002122371: Experimental studies have shown that this variant affects SLC6A8 function (PMID:17465020)." and additional evidence is available in ClinVar. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:2
• Conservation: PhyloP100: 7.97
• Publications: 7 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002122371: Experimental studies have shown that this variant affects SLC6A8 function (PMID: 17465020).; SCV000568381: Published functional studies demonstrate a damaging effect on creatine uptake (Rosenberg et al., 2007)
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005629.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-153690427-TTTC-T is Pathogenic according to our data. Variant chrX-153690427-TTTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21448.Status of the report is reviewed_by_expert_panel, 3 stars.

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.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	Exon 2 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	Exon 2 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.-25_-23delCTT		5_prime_UTR	Exon 2 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.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	Exon 2 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	Exon 2 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.321_323delCTT	p.Phe107del	disruptive_inframe_deletion	Exon 2 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 24

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

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Creatine transporter deficiency (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=50/50	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80338739; hg19: chrX-152955882;