rs1060502808

Variant names:

• chrX-153693321-TCA-T
• rs1060502808
• NM_005629.4:c.974_975delCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005629.4(SLC6A8):​c.974_975delCA​(p.Thr325SerfsTer139) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T325T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 5.98
• Publications: 3 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153693321-TCA-T is Pathogenic according to our data. Variant chrX-153693321-TCA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 410218.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.974_975delCA	p.Thr325SerfsTer139	frameshift	Exon 6 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.974_975delCA	p.Thr325SerfsTer129	frameshift	Exon 6 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.629_630delCA	p.Thr210SerfsTer139	frameshift	Exon 6 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.974_975delCA	p.Thr325SerfsTer139	frameshift	Exon 6 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.974_975delCA	p.Thr325SerfsTer139	frameshift	Exon 6 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.974_975delCA	p.Thr325SerfsTer146	frameshift	Exon 6 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 as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Creatine transporter deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
BranchPoint Hunter		8.0
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060502808; hg19: chrX-152958776;