rs200695210

Variant names:

• chrX-153694528-C-T
• rs200695210
• NM_005629.4:c.1496-5C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005629.4(SLC6A8):​c.1496-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000997 in 1,205,694 control chromosomes in the GnomAD database, including 4 homozygotes. There are 332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., 134 hem., cov: 23)
  • Exomes 𝑓: 0.00064 (0 hom. 198 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004396
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.414

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-153694528-C-T is Benign according to our data. Variant chrX-153694528-C-T is described in ClinVar as [Benign]. Clinvar id is 383235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153694528-C-T is described in Lovd as [Likely_benign]. Variant chrX-153694528-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00449 (499/111068) while in subpopulation AFR AF= 0.0155 (473/30490). AF 95% confidence interval is 0.0144. There are 4 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1496-5C>T		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1466-5C>T		splice_region_variant, intron_variant	Intron 10 of 12		NP_001136277.1
SLC6A8	NM_001142806.1	c.1151-5C>T		splice_region_variant, intron_variant	Intron 10 of 12		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1496-5C>T		splice_region_variant, intron_variant	Intron 10 of 12	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 499 AN: 111016 Hom.: 4 Cov.: 23 AF XY: 0.00403 AC XY: 134 AN XY: 33218

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000758

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: 0.000246

Gnomad OTH AF: 0.00333

GnomAD3 exomes AF: 0.00145 AC: 265 AN: 182957 Hom.: 0 AF XY: 0.000915 AC XY: 62 AN XY: 67753

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000184

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.000642 AC: 703 AN: 1094626 Hom.: 0 Cov.: 33 AF XY: 0.000549 AC XY: 198 AN XY: 360344

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.000909

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000261

Gnomad4 OTH exome AF: 0.000783

GnomAD4 genome AF: 0.00449 AC: 499 AN: 111068 Hom.: 4 Cov.: 23 AF XY: 0.00403 AC XY: 134 AN XY: 33282

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.000757

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000246

Gnomad4 OTH AF: 0.00329

Alfa AF: 0.00234 Hom.: 9

Bravo AF: 0.00499

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Aug 08, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Creatine transporter deficiency Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 14, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.046
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: rs200695210; hg19: chrX-152959983;