X-153693043-C-A

Variant names:

• chrX-153693043-C-A
• rs148232368
• NM_005629.4:c.780C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005629.4(SLC6A8):​c.780C>A​(p.Ile260Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,096,827 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I260I) has been classified as Benign. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.959
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.780C>A	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.780C>A	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.435C>A	p.Ile145Ile	splice_region synonymous	Exon 5 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.780C>A	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.780C>A	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.780C>A	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1096827 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362785

African (AFR) AF: 0.00 AC: 0 AN: 26367

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40431

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3380

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841794

Other (OTH) AF: 0.0000217 AC: 1 AN: 45998

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		-0.96
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: 2

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

Other links and lift over

dbSNP: rs148232368; hg19: chrX-152958498;