rs149024147

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.544G>A variant in SLC6A8 is a missense variant predicted to cause substitution of valine by methionine at amino acid 182 (p.Val182Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (16/19086 alleles) in the African/African American population, meeting the CCDS VCEP’s allele frequency threshold for BS1 (>0.0002) (BS1). This variant is present in 5 or more hemizygotes in gnomAD v2.1.1 (BS2). Furthermore, the variant did not segregate with intellectual disability in multiple brothers, and the proband with the variant had normal urine creatine and normal cerebral creatine on 1H-magnetic resonance spectroscopy (PMID 16738945). The computational predictor REVEL gives a score of 0.184, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact of the variant on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465147). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549204/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., 13 hem., cov: 25)

Exomes 𝑓: 0.000031 ( 0 hom. 12 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 1.43

Publications

3 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.544G>A	p.Val182Met	missense_variant	Exon 3 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.544G>A	p.Val182Met	missense_variant	Exon 3 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.199G>A	p.Val67Met	missense_variant	Exon 3 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.544G>A	p.Val182Met	missense_variant	Exon 3 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.000300

AC:

AN:

113232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000928

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:

0.0000938

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000546

AC:

AN:

183125

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1097592

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

363182

show subpopulations

African (AFR)

AF:

0.000758

AC:

AN:

26387

American (AMR)

AF:

0.00

AC:

AN:

35191

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

841741

Other (OTH)

AF:

0.0000868

AC:

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000300

AC:

AN:

113232

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

AN XY:

35388

show subpopulations

African (AFR)

AF:

0.000928

AC:

AN:

31235

American (AMR)

AF:

0.00

AC:

AN:

10832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3600

South Asian (SAS)

AF:

0.00

AC:

AN:

2815

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000938

AC:

AN:

53289

Other (OTH)

AF:

0.00

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000712

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jun 30, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Apr 24, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Creatine transporter deficiency

Benign:2

Jun 06, 2022

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:c.544G>A variant in SLC6A8 is a missense variant predicted to cause substitution of valine by methionine at amino acid 182 (p.Val182Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (16/19086 alleles) in the African/African American population, meeting the CCDS VCEP’s allele frequency threshold for BS1 (>0.0002) (BS1). This variant is present in 5 or more hemizygotes in gnomAD v2.1.1 (BS2). Furthermore, the variant did not segregate with intellectual disability in multiple brothers, and the proband with the variant had normal urine creatine and normal cerebral creatine on 1H-magnetic resonance spectroscopy (PMID 16738945). The computational predictor REVEL gives a score of 0.184, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact of the variant on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465147). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 28, 2025

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.4

L;.

PhyloP100

1.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.95

N;N

REVEL

Benign

0.18

Sift

Benign

0.19

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.13

B;.

Vest4

0.22

MVP

0.69

MPC

1.3

ClinPred

0.020

GERP RS

3.1

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.24

gMVP

0.64

Mutation Taster

=90/10

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