rs140115896

Variant names:

• chrX-153694388-C-T
• rs140115896
• NM_005629.4:c.1437C>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.1437C>T​(p.Ser479Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000894 in 1,208,861 control chromosomes in the GnomAD database, including 2 homozygotes. There are 331 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 0.0032 (0 hom., 90 hem., cov: 22)
  • Exomes 𝑓: 0.00066 (2 hom. 241 hem.)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.39
• 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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.089).
• BP6: Variant X-153694388-C-T is Benign according to our data. Variant chrX-153694388-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00321 (358/111434) while in subpopulation AFR AF = 0.0108 (331/30627). AF 95% confidence interval is 0.00985. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 90 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.1437C>T	p.Ser479Ser	synonymous	Exon 10 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1407C>T	p.Ser469Ser	synonymous	Exon 10 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1092C>T	p.Ser364Ser	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.1437C>T	p.Ser479Ser	synonymous	Exon 10 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1437C>T	p.Ser479Ser	synonymous	Exon 10 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1428C>T	p.Ser476Ser	synonymous	Exon 10 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 356 AN: 111384 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000566

Gnomad SAS AF: 0.00264

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00134 AC: 245 AN: 183018 AF XY: 0.00124

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000578

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000659 AC: 723 AN: 1097427 Hom.: 2 Cov.: 34 AF XY: 0.000664 AC XY: 241 AN XY: 362913

African (AFR) AF: 0.0128 AC: 338 AN: 26378

American (AMR) AF: 0.000483 AC: 17 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.000298 AC: 9 AN: 30205

South Asian (SAS) AF: 0.00321 AC: 174 AN: 54129

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40492

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4128

European-Non Finnish (NFE) AF: 0.000154 AC: 130 AN: 841455

Other (OTH) AF: 0.00104 AC: 48 AN: 46062

GnomAD4 genome AF: 0.00321 AC: 358 AN: 111434 Hom.: 0 Cov.: 22 AF XY: 0.00268 AC XY: 90 AN XY: 33624

African (AFR) AF: 0.0108 AC: 331 AN: 30627

American (AMR) AF: 0.000848 AC: 9 AN: 10607

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.000568 AC: 2 AN: 3520

South Asian (SAS) AF: 0.00265 AC: 7 AN: 2645

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6045

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 52949

Other (OTH) AF: 0.00199 AC: 3 AN: 1511

Alfa AF: 0.00247 Hom.: 15

Bravo AF: 0.00378

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.86
DANN	Benign	0.69
PhyloP100		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs140115896; hg19: chrX-152959843; COSMIC: COSV107267980; COSMIC: COSV107267980;