X-153694616-AC-A

Variant names:

• chrX-153694616-AC-A
• rs1557045581
• NM_005629.4:c.1583delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.92
• Publications: 1 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, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

Selected	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
	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

Ensembl Transcripts

Selected	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
	SLC6A8	ENST00000430077.6	TSL:2	c.1238delC	p.Pro413ArgfsTer67	frameshift	Exon 11 of 13	ENSP00000403041.2
	SLC6A8	ENST00000485324.1	TSL:2	n.1890delC		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 874531 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 274977

African (AFR) AF: 0.00 AC: 0 AN: 20126

American (AMR) AF: 0.00 AC: 0 AN: 29563

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12527

East Asian (EAS) AF: 0.00 AC: 0 AN: 12794

South Asian (SAS) AF: 0.00 AC: 0 AN: 51502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2606

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 688650

Other (OTH) AF: 0.00 AC: 0 AN: 32230

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Creatine transporter deficiency Pathogenic:1

Sep 30, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1557045581; hg19: chrX-152960071;