rs138064933

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005629.4(SLC6A8):c.813C>T(p.Val271Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,209,832 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,348 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 0.0025 ( 2 hom., 80 hem., cov: 24)

Exomes 𝑓: 0.0034 ( 11 hom. 1268 hem. )

Consequence

SLC6A8
NM_005629.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.488

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

creatine transporter deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050970614).

BP6

Variant X-153693076-C-T is Benign according to our data. Variant chrX-153693076-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.488 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC6A8	NM_005629.4 link	c.813C>T	p.Val271Val	synonymous_variant	Exon 5 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 link	c.813C>T	p.Val271Val	synonymous_variant	Exon 5 of 13		NP_001136277.1
SLC6A8	NM_001142806.1 link	c.468C>T	p.Val156Val	synonymous_variant	Exon 5 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.813C>T	p.Val271Val	synonymous_variant	Exon 5 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

282

AN:

112803

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00252

Gnomad FIN

AF:

0.000958

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00396

GnomAD2 exomes

AF:

0.00336

AC:

613

AN:

182324

AF XY:

0.00347

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.000986

Gnomad ASJ exome

AF:

0.0345

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000818

Gnomad NFE exome

AF:

0.00308

Gnomad OTH exome

AF:

0.00400

GnomAD4 exome

AF:

0.00338

AC:

3705

AN:

1096974

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

1268

AN XY:

362736

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26375

American (AMR)

AF:

0.000994

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.0361

AC:

700

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00263

AC:

142

AN:

54076

European-Finnish (FIN)

AF:

0.000840

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.00366

AC:

AN:

3549

European-Non Finnish (NFE)

AF:

0.00307

AC:

2583

AN:

841709

Other (OTH)

AF:

0.00422

AC:

194

AN:

46009

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

149

299

448

598

747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00248

AC:

280

AN:

112858

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

AN XY:

35016

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

31143

American (AMR)

AF:

0.00158

AC:

AN:

10768

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00253

AC:

AN:

2771

European-Finnish (FIN)

AF:

0.000958

AC:

AN:

6263

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00293

AC:

156

AN:

53244

Other (OTH)

AF:

0.00390

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00651

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00431

AC:

ExAC

AF:

0.00330

AC:

400

EpiCase

AF:

0.00425

EpiControl

AF:

0.00339

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 27, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 29, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Creatine transporter deficiency

Benign:2

Dec 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC6A8-related disorder

Benign:1

Oct 07, 2019

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

Apr 15, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Rhombencephalosynapsis

Benign:1

Apr 17, 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

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.96

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0051

MetaSVM

Uncertain

-0.21

PhyloP100

0.49

PROVEAN

Benign

1.7

REVEL

Benign

0.19

Sift

Pathogenic

0.0

MVP

0.69

ClinPred

0.056

GERP RS

4.9

PromoterAI

0.0076

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over