X-153694445-C-T

Variant names:

• chrX-153694445-C-T
• rs143916832
• NM_005629.4:c.1494C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005629.4(SLC6A8):​c.1494C>T​(p.Tyr498Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,202,327 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,343 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 0.0025 (0 hom., 68 hem., cov: 23)
  • Exomes 𝑓: 0.0037 (7 hom. 1275 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003427
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.53
• 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, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-153694445-C-T is Benign according to our data. Variant chrX-153694445-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00371 (4048/1090716) while in subpopulation NFE AF = 0.00439 (3667/835385). AF 95% confidence interval is 0.00427. There are 7 homozygotes in GnomAdExome4. There are 1275 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 68 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1494C>T	p.Tyr498Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1464C>T	p.Tyr488Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1149C>T	p.Tyr383Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1494C>T	p.Tyr498Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 276 AN: 111561 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000392

Gnomad AMI AF: 0.0324

Gnomad AMR AF: 0.000846

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00261

Gnomad FIN AF: 0.000329

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00215 AC: 393 AN: 182510 AF XY: 0.00197

Gnomad AFR exome AF: 0.000690

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000145

Gnomad FIN exome AF: 0.000563

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.00371 AC: 4048 AN: 1090716 Hom.: 7 Cov.: 34 AF XY: 0.00358 AC XY: 1275 AN XY: 356580

African (AFR) AF: 0.000724 AC: 19 AN: 26234

American (AMR) AF: 0.00136 AC: 48 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19335

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30183

South Asian (SAS) AF: 0.00233 AC: 126 AN: 53976

European-Finnish (FIN) AF: 0.000544 AC: 22 AN: 40459

Middle Eastern (MID) AF: 0.000976 AC: 4 AN: 4097

European-Non Finnish (NFE) AF: 0.00439 AC: 3667 AN: 835385

Other (OTH) AF: 0.00347 AC: 159 AN: 45855

GnomAD4 genome AF: 0.00247 AC: 276 AN: 111611 Hom.: 0 Cov.: 23 AF XY: 0.00201 AC XY: 68 AN XY: 33811

African (AFR) AF: 0.000391 AC: 12 AN: 30686

American (AMR) AF: 0.000845 AC: 9 AN: 10654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3514

South Asian (SAS) AF: 0.00262 AC: 7 AN: 2673

European-Finnish (FIN) AF: 0.000329 AC: 2 AN: 6079

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.00414 AC: 219 AN: 52948

Other (OTH) AF: 0.00197 AC: 3 AN: 1523

Alfa AF: 0.00305 Hom.: 22

Bravo AF: 0.00241

EpiCase AF: 0.00474

EpiControl AF: 0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jul 01, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BS2, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

Aug 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 17, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15154114, 20717164, 16738945) -

Creatine transporter deficiency Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SLC6A8-related disorder Benign:1

May 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Sep 02, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Intellectual disability Benign:1

Nov 26, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.71
DANN	Benign	0.34
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=68/32	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.058
Splicevardb		2.0
SpliceAI score (max)		0.14		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: rs143916832; hg19: chrX-152959900;