X-153695084-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS1BS2BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1778A>G variant in SLC6A8 is a missense variant predicted to cause the substitution of a histidine by an arginine at amino acid position 593 (p.His593Arg). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0., the highest population minor allele frequency is 0.0004421 (20/45238 alleles; 2 homozygotes, 0 hemizygotes) in the Admixed American population. This MAF is higher than the ClinGen CCDS VCEP's threshold for BS1 (>0.0002), meeting this criterion (BS1). Overall, across all populations, there are 3 homozygotes and 7 hemizygotes in gnomAD v4.1.0. (BS2). The computational predictor REVEL gives a score of 0.133 suggesting that the variant has no impact on protein function. SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465144). In summary, this variant meets criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549662/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.00028 ( 2 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000027 ( 1 hom. 6 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.15

Publications

1 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 -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1778A>G	p.His593Arg	missense_variant	Exon 13 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1748A>G	p.His583Arg	missense_variant	Exon 13 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1433A>G	p.His478Arg	missense_variant	Exon 13 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.1778A>G	p.His593Arg	missense_variant	Exon 13 of 13	1	NM_005629.4	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000430077.6 link	c.1433A>G	p.His478Arg	missense_variant	Exon 13 of 13	2		ENSP00000403041.2	P48029-4
SLC6A8	ENST00000485324.1 link	n.2085A>G		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

112504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00186

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000560

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00464

GnomAD2 exomes

AF:

0.0000306

AC:

AN:

163260

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000156

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000487

GnomAD4 exome

AF:

0.0000266

AC:

AN:

1089595

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

356981

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26256

American (AMR)

AF:

0.00

AC:

AN:

34490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19194

East Asian (EAS)

AF:

0.000134

AC:

AN:

29896

South Asian (SAS)

AF:

0.00

AC:

AN:

52717

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.00000358

AC:

AN:

837900

Other (OTH)

AF:

0.000482

AC:

AN:

45686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000284

AC:

AN:

112558

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34746

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31017

American (AMR)

AF:

0.00186

AC:

AN:

10748

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.000562

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6241

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53164

Other (OTH)

AF:

0.00655

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000746

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Uncertain:1Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC6A8-related disorder

Benign:1

Sep 04, 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 26, 2023

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. -

not provided

Benign:1

Jul 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.082

T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

N;.

PhyloP100

2.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.13

Sift

Benign

0.37

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0010

B;.

Vest4

0.10

MutPred

0.44

Gain of MoRF binding (P = 0.0059);.;

MVP

0.70

MPC

0.18

ClinPred

0.031

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.78

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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