rs201581661

Positions:

• chrX-153692111-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005629.4(SLC6A8):​c.777+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,197,742 control chromosomes in the GnomAD database, including 1 homozygotes. There are 274 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., 16 hem., cov: 24)
  • Exomes 𝑓: 0.00074 (1 hom. 258 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.001010
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.793

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-153692111-C-T is Benign according to our data. Variant chrX-153692111-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 380584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153692111-C-T is described in Lovd as [Benign]. Variant chrX-153692111-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.777+4C>T		splice_donor_region_variant, intron_variant		ENST00000253122.10
SLC6A8	NM_001142805.2	c.777+4C>T		splice_donor_region_variant, intron_variant
SLC6A8	NM_001142806.1	c.432+4C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.777+4C>T		splice_donor_region_variant, intron_variant		1	NM_005629.4	P1

Frequencies

GnomAD3 genomes AF: 0.000569 AC: 64 AN: 112396 Hom.: 0 Cov.: 24 AF XY: 0.000463 AC XY: 16 AN XY: 34592

Gnomad AFR AF: 0.000226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000960

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.000538 AC: 88 AN: 163556 Hom.: 1 AF XY: 0.000545 AC XY: 28 AN XY: 51378

Gnomad AFR exome AF: 0.0000818

Gnomad AMR exome AF: 0.000193

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000759

Gnomad SAS exome AF: 0.000129

Gnomad FIN exome AF: 0.000481

Gnomad NFE exome AF: 0.000880

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000742 AC: 805 AN: 1085346 Hom.: 1 Cov.: 30 AF XY: 0.000732 AC XY: 258 AN XY: 352486

Gnomad4 AFR exome AF: 0.0000381

Gnomad4 AMR exome AF: 0.000175

Gnomad4 ASJ exome AF: 0.000746

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000384

Gnomad4 FIN exome AF: 0.000551

Gnomad4 NFE exome AF: 0.000869

Gnomad4 OTH exome AF: 0.000681

GnomAD4 genome AF: 0.000569 AC: 64 AN: 112396 Hom.: 0 Cov.: 24 AF XY: 0.000463 AC XY: 16 AN XY: 34592

Gnomad4 AFR AF: 0.000226

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000160

Gnomad4 NFE AF: 0.000960

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00113 Hom.: 9

Bravo AF: 0.000536

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SLC6A8: BP4, BS2 -

Creatine transporter deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

SLC6A8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 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). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2016

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
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.5
DANN	Benign	0.97
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.17
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

Other links and lift over

dbSNP: rs201581661; hg19: chrX-152957566;