rs782694291

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1

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

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 links:

SLC6A8 (HGNC:):

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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	MANE	Protein	UniProt
SLC6A8	NM_005629.4 linkuse as main transcript	c.912+9G>A	intron_variant	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 linkuse as main transcript	c.912+9G>A	intron_variant		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 linkuse as main transcript	c.567+9G>A	intron_variant		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.912+9G>A		intron_variant		1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.0000974

AC:

AN:

112907

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

35049

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

GnomAD3 exomes

AF:

0.000619

AC:

112

AN:

181006

Hom.:

AF XY:

0.000362

AC XY:

AN XY:

66282

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00344

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000974

AC:

AN:

112907

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

35049

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00102

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	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

Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	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). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.84

DANN

Benign

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over