X-153694748-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.1626C>T(p.Tyr542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,209,756 control chromosomes in the GnomAD database, including 1 homozygotes. There are 57 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 0.00040 (0 hom., 8 hem., cov: 25)
  • Exomes 𝑓: 0.00016 (1 hom. 49 hem.)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0440

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=-0.66).
• BP6: Variant X-153694748-C-T is Benign according to our data. Variant chrX-153694748-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.044 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1626C>T	p.Tyr542=	synonymous_variant	12/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1596C>T	p.Tyr532=	synonymous_variant	12/13
SLC6A8	NM_001142806.1	c.1281C>T	p.Tyr427=	synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1626C>T	p.Tyr542=	synonymous_variant	12/13	1	NM_005629.4	P1
SLC6A8	ENST00000430077.6	c.1281C>T	p.Tyr427=	synonymous_variant	12/13	2
SLC6A8	ENST00000485324.1	n.1933C>T		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.000400 AC: 45 AN: 112553 Hom.: 0 Cov.: 25 AF XY: 0.000230 AC XY: 8 AN XY: 34717

Gnomad AFR AF: 0.00103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000208 AC: 38 AN: 182414 Hom.: 1 AF XY: 0.000148 AC XY: 10 AN XY: 67534

Gnomad AFR exome AF: 0.000919

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: 0.000313

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000157 AC: 172 AN: 1097153 Hom.: 1 Cov.: 38 AF XY: 0.000135 AC XY: 49 AN XY: 362897

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.000248

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000400 AC: 45 AN: 112603 Hom.: 0 Cov.: 25 AF XY: 0.000230 AC XY: 8 AN XY: 34777

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000582 Hom.: 3

Bravo AF: 0.000412

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SLC6A8: BP4, BP7 -

Creatine transporter deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Creatine deficiency syndrome 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 06, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2018

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	-0.66
Cadd	Benign	0.088
Dann	Benign	0.36
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

Other links and lift over

dbSNP: rs140601882; hg19: chrX-152960203; COSMIC: COSV53471673; COSMIC: COSV53471673;