X-153694445-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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:13

Conservation

PhyloP100: -2.53

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chrX-153694445-C-T is described in Lovd as [Benign]. Variant chrX-153694445-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.53 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 1275 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

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 link	c.1494C>T	p.Tyr498Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1464C>T	p.Tyr488Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1149C>T	p.Tyr383Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.1494C>T	p.Tyr498Tyr	splice_region_variant, synonymous_variant	Exon 10 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

276

AN:

111561

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

AN XY:

33751

show subpopulations

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

GnomAD3 exomes

AF:

0.00215

AC:

393

AN:

182510

Hom.:

AF XY:

0.00197

AC XY:

133

AN XY:

67526

show subpopulations

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 SAS exome

AF:

0.00273

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.:

Cov.:

AF XY:

0.00358

AC XY:

1275

AN XY:

356580

show subpopulations

Gnomad4 AFR exome

AF:

0.000724

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.00233

Gnomad4 FIN exome

AF:

0.000544

Gnomad4 NFE exome

AF:

0.00439

Gnomad4 OTH exome

AF:

0.00347

GnomAD4 genome

AF:

0.00247

AC:

276

AN:

111611

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

AN XY:

33811

show subpopulations

Gnomad4 AFR

AF:

0.000391

Gnomad4 AMR

AF:

0.000845

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000285

Gnomad4 SAS

AF:

0.00262

Gnomad4 FIN

AF:

0.000329

Gnomad4 NFE

AF:

0.00414

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.00305

Hom.:

Bravo

AF:

0.00241

EpiCase

AF:

0.00474

EpiControl

AF:

0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

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). -

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

- -

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) -

May 17, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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

- -

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. -

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.71

DANN

Benign

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00034

dbscSNV1_RF

Benign

0.058

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over