rs376038235

Variant names:

• chrX-153694525-C-T
• rs376038235
• NM_005629.4:c.1496-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005629.4(SLC6A8):​c.1496-8C>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 0.000437 in 1,204,764 control chromosomes in the GnomAD database, including 1 homozygotes. There are 172 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., 18 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (1 hom. 154 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007151
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.07
• Publications: 5 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.011).
• BP6: Variant X-153694525-C-T is Benign according to our data. Variant chrX-153694525-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000486 (54/111076) while in subpopulation EAS AF = 0.0117 (41/3513). AF 95% confidence interval is 0.00884. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 18 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.1496-8C>T		splice_region intron	N/A	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1466-8C>T		splice_region intron	N/A	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1151-8C>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.1496-8C>T		splice_region intron	N/A	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1496-11C>T		intron	N/A	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1487-8C>T		splice_region intron	N/A	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.000468 AC: 52 AN: 111022 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000986

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0111

Gnomad SAS AF: 0.000380

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000114

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 190 AN: 182929 AF XY: 0.000974

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000982

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000432 AC: 472 AN: 1093688 Hom.: 1 Cov.: 33 AF XY: 0.000428 AC XY: 154 AN XY: 359448

African (AFR) AF: 0.000228 AC: 6 AN: 26304

American (AMR) AF: 0.0000284 AC: 1 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19358

East Asian (EAS) AF: 0.0115 AC: 346 AN: 30188

South Asian (SAS) AF: 0.000204 AC: 11 AN: 54025

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.000106 AC: 89 AN: 838121

Other (OTH) AF: 0.000414 AC: 19 AN: 45937

GnomAD4 genome AF: 0.000486 AC: 54 AN: 111076 Hom.: 0 Cov.: 22 AF XY: 0.000541 AC XY: 18 AN XY: 33296

African (AFR) AF: 0.0000984 AC: 3 AN: 30493

American (AMR) AF: 0.000283 AC: 3 AN: 10594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.0117 AC: 41 AN: 3513

South Asian (SAS) AF: 0.000381 AC: 1 AN: 2625

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000114 AC: 6 AN: 52774

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.000364 Hom.: 2

Bravo AF: 0.000544

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Creatine transporter deficiency (2)
-	-	2	not specified (2)
-	-	1	Creatine deficiency syndrome 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.40
PhyloP100		-2.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.11
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: rs376038235; hg19: chrX-152959980;