X-153693043-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005629.4(SLC6A8):​c.780C>T​(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 0.000329 in 1,209,720 control chromosomes in the GnomAD database, including 1 homozygotes. There are 118 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., 53 hem., cov: 25)
  • Exomes 𝑓: 0.00019 (0 hom. 65 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-153693043-C-T is Benign according to our data. Variant chrX-153693043-C-T is described in ClinVar as Benign. ClinVar VariationId is 383165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.959 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00168 (190/112892) while in subpopulation AFR AF = 0.00584 (182/31163). AF 95% confidence interval is 0.00515. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 53 XL gene

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

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 190 AN: 112838 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.00585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.000428 AC: 78 AN: 182298 AF XY: 0.000401

Gnomad AFR exome AF: 0.00482

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000190 AC: 208 AN: 1096828 Hom.: 0 Cov.: 32 AF XY: 0.000179 AC XY: 65 AN XY: 362786

African (AFR) AF: 0.00565 AC: 149 AN: 26367

American (AMR) AF: 0.000511 AC: 18 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: 0.0000370 AC: 2 AN: 54085

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

Middle Eastern (MID) AF: 0.000296 AC: 1 AN: 3380

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 841794

Other (OTH) AF: 0.000565 AC: 26 AN: 45998

GnomAD4 genome AF: 0.00168 AC: 190 AN: 112892 Hom.: 1 Cov.: 25 AF XY: 0.00151 AC XY: 53 AN XY: 35072

African (AFR) AF: 0.00584 AC: 182 AN: 31163

American (AMR) AF: 0.000463 AC: 5 AN: 10800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53232

Other (OTH) AF: 0.00196 AC: 3 AN: 1533

Alfa AF: 0.00164 Hom.: 6

Bravo AF: 0.00200

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Creatine transporter deficiency (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.7
DANN	Benign	0.89
PhyloP100		-0.96
PromoterAI		-0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs148232368; hg19: chrX-152958498; COSMIC: COSV53473467; COSMIC: COSV53473467;