rs201260657

chrX-153691407-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005629.4(SLC6A8):c.498G>A(p.Thr166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,209,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 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 0.000053 (0 hom., 2 hem., cov: 25)
  • Exomes 𝑓: 0.000056 (0 hom. 17 hem.)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.891

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-153691407-G-A is Benign according to our data. Variant chrX-153691407-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.891 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.498G>A	p.Thr166=	synonymous_variant	3/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.498G>A	p.Thr166=	synonymous_variant	3/13
SLC6A8	NM_001142806.1	c.153G>A	p.Thr51=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.498G>A	p.Thr166=	synonymous_variant	3/13	1	NM_005629.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 6 AN: 112909 Hom.: 0 Cov.: 25 AF XY: 0.0000570 AC XY: 2 AN XY: 35093

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000926

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000930 AC: 17 AN: 182870 Hom.: 0 AF XY: 0.0000739 AC XY: 5 AN XY: 67618

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000737

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.0000556 AC: 61 AN: 1096991 Hom.: 0 Cov.: 30 AF XY: 0.0000469 AC XY: 17 AN XY: 362571

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000499

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000531 AC: 6 AN: 112959 Hom.: 0 Cov.: 25 AF XY: 0.0000569 AC XY: 2 AN XY: 35153

Gnomad4 AFR AF: 0.0000321

Gnomad4 AMR AF: 0.0000925

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 18, 2019

- -

Creatine transporter deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	7.2
Dann	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs201260657; hg19: chrX-152956862;