rs150207268

Variant names:

• chrX-153695071-C-T
• rs150207268
• NM_005629.4:c.1768-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005629.4(SLC6A8):​c.1768-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,198,729 control chromosomes in the GnomAD database, including 18 homozygotes. There are 2,195 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0043 (0 hom., 144 hem., cov: 23)
  • Exomes 𝑓: 0.0060 (18 hom. 2051 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, intron
• Scores: Splicing: ADA: 0.07024
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.07
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-153695071-C-T is Benign according to our data. Variant chrX-153695071-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00435 (490/112720) while in subpopulation AMR AF = 0.0078 (84/10773). AF 95% confidence interval is 0.00645. There are 0 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 144 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.1768-3C>T		splice_region intron	N/A	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1738-3C>T		splice_region intron	N/A	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1423-3C>T		splice_region intron	N/A	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.1768-3C>T		splice_region intron	N/A	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1765-3C>T		splice_region intron	N/A	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1759-3C>T		splice_region intron	N/A	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 490 AN: 112668 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000516

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.00781

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000725

Gnomad FIN AF: 0.00112

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.00445 AC: 709 AN: 159238 AF XY: 0.00404

Gnomad AFR exome AF: 0.000445

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00160

Gnomad NFE exome AF: 0.00701

Gnomad OTH exome AF: 0.00797

GnomAD4 exome AF: 0.00604 AC: 6559 AN: 1086009 Hom.: 18 Cov.: 31 AF XY: 0.00579 AC XY: 2051 AN XY: 354315

African (AFR) AF: 0.000496 AC: 13 AN: 26187

American (AMR) AF: 0.00298 AC: 102 AN: 34208

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 265 AN: 19087

East Asian (EAS) AF: 0.00 AC: 0 AN: 29767

South Asian (SAS) AF: 0.000804 AC: 42 AN: 52239

European-Finnish (FIN) AF: 0.00178 AC: 70 AN: 39380

Middle Eastern (MID) AF: 0.0129 AC: 49 AN: 3792

European-Non Finnish (NFE) AF: 0.00688 AC: 5753 AN: 835791

Other (OTH) AF: 0.00582 AC: 265 AN: 45558

GnomAD4 genome AF: 0.00435 AC: 490 AN: 112720 Hom.: 0 Cov.: 23 AF XY: 0.00413 AC XY: 144 AN XY: 34876

African (AFR) AF: 0.000515 AC: 16 AN: 31054

American (AMR) AF: 0.00780 AC: 84 AN: 10773

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 37 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.000727 AC: 2 AN: 2750

European-Finnish (FIN) AF: 0.00112 AC: 7 AN: 6277

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.00622 AC: 331 AN: 53213

Other (OTH) AF: 0.00261 AC: 4 AN: 1530

Alfa AF: 0.00698 Hom.: 56

Bravo AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Creatine transporter deficiency (2)
-	-	1	Creatine deficiency syndrome 1 (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	-0.39
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.070
dbscSNV1_RF	Benign	0.23
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: rs150207268; hg19: chrX-152960526;