dbSNP rs1557045581: SLC6A8:p.Pro528ArgfsTer67 (chrX-153694616-AC-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_005629.4(SLC6A8):c.1583delC(p.Pro528ArgfsTer67) 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. P528P) has been classified as Benign. Variant results in nonsense mediated mRNA decay. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.92

Publications

1 publications found

Variant links:

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

SLC6A8 links:

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ACMG classification

Specifications for SLC6A8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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-153694616-AC-A is Pathogenic according to our data. Variant chrX-153694616-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 436772.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	NM_005629.4	MANE Select	c.1583delC	p.Pro528ArgfsTer67	frameshift	Exon 11 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.1553delC	p.Pro518ArgfsTer67	frameshift	Exon 11 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.1238delC	p.Pro413ArgfsTer67	frameshift	Exon 11 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1583delC	p.Pro528ArgfsTer67	frameshift	Exon 11 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.1580delC	p.Pro527ArgfsTer67	frameshift	Exon 11 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.1574delC	p.Pro525ArgfsTer67	frameshift	Exon 11 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

874531

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

274977

African (AFR)

AF:

0.00

AC:

AN:

20126

American (AMR)

AF:

0.00

AC:

AN:

29563

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12527

East Asian (EAS)

AF:

0.00

AC:

AN:

12794

South Asian (SAS)

AF:

0.00

AC:

AN:

51502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2606

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

688650

Other (OTH)

AF:

0.00

AC:

AN:

32230

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over