rs782694291

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.912+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 5. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004083 in the Latino/Admixed American population, meeting the ClinGen CCDS VCEP allele frequency threshold for BS1 (>0.0002) (BS1). The variant is present in 25 hemizygotes and 2 homozygotes in gnomAD v2.1.1 (BS2). The computational predictor, SpliceAI, predicts that the variant has no impact on splicing, and varSEAK indicates an unknown effect on splicing due to possible strengthening of a cryptic splice site in intron 5. To our knowledge, this variant has not been reported in any patients with features of creatine transporter deficiency the literature and no results of functional or splicing assays are unavailable. There is a ClinVar entry for this variant (Variation ID: 383888). In summary, this variant meets the 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.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549344/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.00011 ( 2 hom. 26 hem. )

Consequence

SLC6A8
NM_005629.4 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -0.0590

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 -8 ACMG points.

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	Effect	Exon rank	MANE	Protein
SLC6A8	NM_005629.4 link	c.912+9G>A	intron_variant	Intron 5 of 12	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 link	c.912+9G>A	intron_variant	Intron 5 of 12		NP_001136277.1
SLC6A8	NM_001142806.1 link	c.567+9G>A	intron_variant	Intron 5 of 12		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.912+9G>A		intron_variant	Intron 5 of 12	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes

AF:

0.0000974

AC:

AN:

112907

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00102

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000619

AC:

112

AN:

181006

AF XY:

0.000362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

123

AN:

1097043

Hom.:

Cov.:

AF XY:

0.0000717

AC XY:

AN XY:

362635

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26375

American (AMR)

AF:

0.00344

AC:

121

AN:

35171

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54087

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3811

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841563

Other (OTH)

AF:

0.0000435

AC:

AN:

46010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000974

AC:

AN:

112907

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

35049

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31120

American (AMR)

AF:

0.00102

AC:

AN:

10802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3582

South Asian (SAS)

AF:

0.00

AC:

AN:

2785

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6279

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53237

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000253

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 26, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Creatine transporter deficiency

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.912+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 5. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004083 in the Latino/Admixed American population, meeting the ClinGen CCDS VCEP allele frequency threshold for BS1 (>0.0002) (BS1). The variant is present in 25 hemizygotes and 2 homozygotes in gnomAD v2.1.1 (BS2). The computational predictor, SpliceAI, predicts that the variant has no impact on splicing, and varSEAK indicates an unknown effect on splicing due to possible strengthening of a cryptic splice site in intron 5. To our knowledge, this variant has not been reported in any patients with features of creatine transporter deficiency the literature and no results of functional or splicing assays are unavailable. There is a ClinVar entry for this variant (Variation ID: 383888). In summary, this variant meets the 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. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.84

(source)

DANN

Benign

0.82

PhyloP100

-0.059

PromoterAI

0.0054

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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