NM_005629.4:c.1162G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.1162G>A (p.Ala388Thr) variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Alanine at amino acid 338 (p.Ala338Thr). There is a ClinVar entry for this variant (Variation ID:436771). This variant is found with an allele frequency of 0.003854 in gnomADv2.1.1 with 17 hemizygotes present in that population database. Given the presence of >10 hemizygotes in gnomADv2.1.1 and an allele frequency >0.002, the stand alone benign criteria BA1 is applicable for this variant. In summary, this variant meets the criteria to be classified as Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0; ; classification approved Feb 23, 2023): BA1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549443/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 8 hem., cov: 24)

Exomes 𝑓: 0.00048 ( 1 hom. 153 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: 9.85

Publications

4 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 -8 ACMG points.

BA1

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.1162G>A	p.Ala388Thr	missense_variant	Exon 8 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1132G>A	p.Ala378Thr	missense_variant	Exon 8 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.817G>A	p.Ala273Thr	missense_variant	Exon 8 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.1162G>A	p.Ala388Thr	missense_variant	Exon 8 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

112742

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000279

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000642

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000432

Gnomad OTH

AF:

0.000657

GnomAD2 exomes

AF:

0.000330

AC:

AN:

118182

AF XY:

0.000321

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00109

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000479

AC:

504

AN:

1053227

Hom.:

Cov.:

AF XY:

0.000446

AC XY:

153

AN XY:

342745

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25128

American (AMR)

AF:

0.0000353

AC:

AN:

28368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18659

East Asian (EAS)

AF:

0.00

AC:

AN:

27609

South Asian (SAS)

AF:

0.0000200

AC:

AN:

50062

European-Finnish (FIN)

AF:

0.000911

AC:

AN:

37308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2918

European-Non Finnish (NFE)

AF:

0.000561

AC:

459

AN:

818837

Other (OTH)

AF:

0.000203

AC:

AN:

44338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000301

AC:

AN:

112795

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

34941

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

31106

American (AMR)

AF:

0.000278

AC:

AN:

10778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3550

South Asian (SAS)

AF:

0.00

AC:

AN:

2759

European-Finnish (FIN)

AF:

0.000642

AC:

AN:

6230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000432

AC:

AN:

53268

Other (OTH)

AF:

0.000649

AC:

AN:

1542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000485

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000453

AC:

ExAC

AF:

0.0000943

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Feb 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Creatine transporter deficiency

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_005629.4(SLC6A8):c.1162G>A (p.Ala388Thr) variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Alanine at amino acid 338 (p.Ala338Thr). There is a ClinVar entry for this variant (Variation ID:436771). This variant is found with an allele frequency of 0.003854 in gnomADv2.1.1 with 17 hemizygotes present in that population database. Given the presence of >10 hemizygotes in gnomADv2.1.1 and an allele frequency >0.002, the stand alone benign criteria BA1 is applicable for this variant. In summary, this variant meets the criteria to be classified as Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0; ; classification approved Feb 23, 2023): BA1 -

not provided

Benign:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC6A8: PP2, BS2 -

Mar 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as a non-pathogenic variant in a male with intellectual disability and normal creatine uptake in cultured skin fibroblasts (Betsalel et al, 2011).; This variant is associated with the following publications: (PMID: 28758966, 22281021, 26684475, 20717164, 25861866) -

Creatine deficiency syndrome 1

Benign:1

Jan 24, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 05, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;.

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

9.8

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.020

D;T

Polyphen

0.97

D;.

Vest4

0.61

MVP

0.93

MPC

2.3

ClinPred

0.31

GERP RS

4.8

PromoterAI

-0.045

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.83

gMVP

0.82

Mutation Taster

=82/18

polymorphism

(source)

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

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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