X-153693375-C-T

Position:

chrX-153693375-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1016+9C>T variant in SLC6A8 is an intronic variant in the region of the donor splice site of intron 6. The total number of hemizygotes in gnomAD v2.1.1 is 46, meeting the ClinGen CCDS VCEP’s threshold for BA1 (>10 hemizygotes). The highest minor allele frequency is 0.0009212 (European non-Finnish) with 39 hemizygotes in that population (BA1). The computational predictors SpliceAI and varSEAK predict that the variant has no impact in splicing (BP4). There is a ClinVar entry for the variant (Variation ID: 379398). 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): BA1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549374/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., 21 hem., cov: 24)

Exomes 𝑓: 0.00072 ( 1 hom. 252 hem. )

Consequence

SLC6A8
ENST00000253122.10 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -0.149

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
SLC6A8	NM_005629.4 linkuse as main transcript	c.1016+9C>T	intron_variant	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 linkuse as main transcript	c.1016+9C>T	intron_variant		NP_001136277.1
SLC6A8	NM_001142806.1 linkuse as main transcript	c.671+9C>T	intron_variant		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.1016+9C>T		intron_variant		1	NM_005629.4	ENSP00000253122	P1	P48029-1

Frequencies

GnomAD3 genomes

AF:

0.000472

AC:

AN:

112206

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

AN XY:

34382

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000187

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000321

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000827

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000558

AC:

102

AN:

182927

Hom.:

AF XY:

0.000620

AC XY:

AN XY:

67737

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00100

Gnomad NFE exome

AF:

0.000969

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000716

AC:

782

AN:

1091882

Hom.:

Cov.:

AF XY:

0.000705

AC XY:

252

AN XY:

357570

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.000833

Gnomad4 OTH exome

AF:

0.000523

GnomAD4 genome

AF:

0.000472

AC:

AN:

112258

Hom.:

Cov.:

AF XY:

0.000610

AC XY:

AN XY:

34444

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.000187

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000321

Gnomad4 NFE

AF:

0.000827

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000434

Hom.:

Bravo

AF:

0.000491

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_005629.4:c.1016+9C>T variant in SLC6A8 is an intronic variant in the region of the donor splice site of intron 6. The total number of hemizygotes in gnomAD v2.1.1 is 46, meeting the ClinGen CCDS VCEP’s threshold for BA1 (>10 hemizygotes). The highest minor allele frequency is 0.0009212 (European non-Finnish) with 39 hemizygotes in that population (BA1). The computational predictors SpliceAI and varSEAK predict that the variant has no impact in splicing (BP4). There is a ClinVar entry for the variant (Variation ID: 379398). 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): BA1, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 03, 2018

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. -

SLC6A8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.3

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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