rs1557045296

Variant names:

• chrX-153693971-C-T
• rs1557045296
• NM_005629.4:c.1208C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_005629.4(SLC6A8):​c.1208C>T​(p.Ala403Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.80
• 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

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005629.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant X-153693971-C-T is Pathogenic according to our data. Variant chrX-153693971-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523485.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1208C>T	p.Ala403Val	missense	Exon 8 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1178C>T	p.Ala393Val	missense	Exon 8 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.863C>T	p.Ala288Val	missense	Exon 8 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.1208C>T	p.Ala403Val	missense	Exon 8 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1208C>T	p.Ala403Val	missense	Exon 8 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1208C>T	p.Ala403Val	missense	Exon 8 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1064367 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 345973

African (AFR) AF: 0.00 AC: 0 AN: 25691

American (AMR) AF: 0.00 AC: 0 AN: 30100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18818

East Asian (EAS) AF: 0.00 AC: 0 AN: 28532

South Asian (SAS) AF: 0.00 AC: 0 AN: 50827

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3103

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 824544

Other (OTH) AF: 0.00 AC: 0 AN: 44788

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Seizure;C0239234:Low-set ears;C0424503:Abnormal facial shape;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.74	P
Vest4		0.78
MutPred		0.72		Loss of glycosylation at P400 (P = 0.2724)
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.97
Mutation Taster		=4/96	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: rs1557045296; hg19: chrX-152959426;