rs781962672

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1025T>C variant in SLC6A8 is a missense variant predicted to cause the substitution of an isoleucine by a threonine at amino acid position 342 (p.Ile342Thr). 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 (MAF) is 0.00005812 (52/894699; 14 hemizygotes) in the European non-Finnish population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is a total of 16 hemizygotes in gnomAD v4.1.0.; 14 in the European non-Finnish population and 2 in the "remaining" population (BS2). The computational predictor REVEL gives a score of 0.64 (PP3), which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 448419). Due to the presence of 16 hemizygotes in gnomAD v4.1.0 in the absence of any evidence for pathogenicity, the consensus of the ClinGen CCDS VCEP is to classify this variant as likely benign for creatine transporter deficiency, a severe, pediatric onset neurodevelopmental disorder. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2(Classification approved by the ClinGen CCDS VCEP on April 11, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549409/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000049 ( 0 hom. 16 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:3

Conservation

PhyloP100: 3.47

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BS2

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC6A8	NM_005629.4	MANE Select	c.1025T>C	p.Ile342Thr	missense	Exon 7 of 13	NP_005620.1
SLC6A8	NM_001142806.1		c.680T>C	p.Ile227Thr	missense	Exon 7 of 13	NP_001136278.1
SLC6A8	NM_001142805.2		c.1017-22T>C		intron	N/A	NP_001136277.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1025T>C	p.Ile342Thr	missense	Exon 7 of 13	ENSP00000253122.5
SLC6A8	ENST00000955775.1		c.1025T>C	p.Ile342Thr	missense	Exon 7 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.1025T>C	p.Ile342Thr	missense	Exon 7 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

111521

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183371

AF XY:

0.0000147

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:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000492

AC:

AN:

1097689

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

363081

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26391

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4105

European-Non Finnish (NFE)

AF:

0.0000547

AC:

AN:

841692

Other (OTH)

AF:

0.000174

AC:

AN:

46070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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

<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:

0.0000538

AC:

AN:

111521

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33743

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30671

American (AMR)

AF:

0.00

AC:

AN:

10553

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53007

Other (OTH)

AF:

0.00

AC:

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (2)

not specified (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.1

PhyloP100

3.5

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.37

Vest4

0.61

MutPred

0.68

Loss of stability (P = 0.0086)

MVP

0.96

MPC

1.9

ClinPred

0.31

GERP RS

5.5

BranchPoint Hunter

4.0

PromoterAI

-0.087

Neutral

(source)

Varity_R

0.67

gMVP

0.82

Mutation Taster

=85/15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over