chrX-153694424-C-T

Variant names:

• chrX-153694424-C-T
• rs122453118
• NM_005629.4:c.1473C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005629.4(SLC6A8):​c.1473C>T​(p.Cys491Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,206,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 64 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00017 (0 hom. 63 hem.)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.298
• Publications: 7 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-153694424-C-T is Benign according to our data. Variant chrX-153694424-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.298 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 63 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.1473C>T	p.Cys491Cys	synonymous	Exon 10 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1443C>T	p.Cys481Cys	synonymous	Exon 10 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1128C>T	p.Cys376Cys	synonymous	Exon 10 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.1473C>T	p.Cys491Cys	synonymous	Exon 10 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1473C>T	p.Cys491Cys	synonymous	Exon 10 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1464C>T	p.Cys488Cys	synonymous	Exon 10 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111339 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000982

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.000668

GnomAD2 exomes AF: 0.000120 AC: 22 AN: 182616 AF XY: 0.000148

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000172 AC: 188 AN: 1094804 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 63 AN XY: 360394

African (AFR) AF: 0.0000759 AC: 2 AN: 26334

American (AMR) AF: 0.0000284 AC: 1 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30196

South Asian (SAS) AF: 0.0000555 AC: 3 AN: 54069

European-Finnish (FIN) AF: 0.000272 AC: 11 AN: 40477

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4108

European-Non Finnish (NFE) AF: 0.000187 AC: 157 AN: 839079

Other (OTH) AF: 0.000196 AC: 9 AN: 45975

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111339 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33557

African (AFR) AF: 0.0000982 AC: 3 AN: 30550

American (AMR) AF: 0.00 AC: 0 AN: 10601

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2663

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6031

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 52917

Other (OTH) AF: 0.000668 AC: 1 AN: 1497

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.0000907

EpiCase AF: 0.00

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs122453118; hg19: chrX-152959879; COSMIC: COSV53471733; COSMIC: COSV53471733;