rs140115896

chrX-153694388-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005629.4(SLC6A8):c.1437C>T(p.Ser479=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000894 in 1,208,861 control chromosomes in the GnomAD database, including 2 homozygotes. There are 331 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 0.0032 (0 hom., 90 hem., cov: 22)
  • Exomes 𝑓: 0.00066 (2 hom. 241 hem.)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.39

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-153694388-C-T is Benign according to our data. Variant chrX-153694388-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153694388-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00321 (358/111434) while in subpopulation AFR AF= 0.0108 (331/30627). AF 95% confidence interval is 0.00985. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 89 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1437C>T	p.Ser479=	synonymous_variant	10/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.1407C>T	p.Ser469=	synonymous_variant	10/13
SLC6A8	NM_001142806.1	c.1092C>T	p.Ser364=	synonymous_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1437C>T	p.Ser479=	synonymous_variant	10/13	1	NM_005629.4	P1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 356 AN: 111384 Hom.: 0 Cov.: 22 AF XY: 0.00265 AC XY: 89 AN XY: 33564

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000566

Gnomad SAS AF: 0.00264

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.00134 AC: 245 AN: 183018 Hom.: 0 AF XY: 0.00124 AC XY: 84 AN XY: 67724

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000578

Gnomad SAS exome AF: 0.00309

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000659 AC: 723 AN: 1097427 Hom.: 2 Cov.: 34 AF XY: 0.000664 AC XY: 241 AN XY: 362913

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000298

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00321 AC: 358 AN: 111434 Hom.: 0 Cov.: 22 AF XY: 0.00268 AC XY: 90 AN XY: 33624

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.000848

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000568

Gnomad4 SAS AF: 0.00265

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00199

Alfa AF: 0.00247 Hom.: 15

Bravo AF: 0.00378

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 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. -

Creatine transporter deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2016

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.86
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs140115896; hg19: chrX-152959843;