rs376421364

chrX-153694403-C-GchrX-153694403-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005629.4(SLC6A8):c.1452C>G(p.Leu484=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,208,822 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L484L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 48 hem.)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.574

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-153694403-C-G is Benign according to our data. Variant chrX-153694403-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 382728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.574 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1452C>G	p.Leu484=	synonymous_variant	10/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1422C>G	p.Leu474=	synonymous_variant	10/13
SLC6A8	NM_001142806.1	c.1107C>G	p.Leu369=	synonymous_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1452C>G	p.Leu484=	synonymous_variant	10/13	1	NM_005629.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000807 AC: 9 AN: 111551 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33727

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000943

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: 0.000151

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 182849 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67703

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000614

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 150 AN: 1097271 Hom.: 0 Cov.: 34 AF XY: 0.000132 AC XY: 48 AN XY: 362753

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

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: 0.000172

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.0000807 AC: 9 AN: 111551 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33727

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000943

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	SLC6A8: BP4, BP7 -

Creatine transporter deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2019

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	-0.55
Cadd	Benign	3.5
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376421364; hg19: chrX-152959858;