rs376038235

chrX-153694525-C-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.1496-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,204,764 control chromosomes in the GnomAD database, including 1 homozygotes. There are 172 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., 18 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (1 hom. 154 hem.)
• Consequence: SLC6A8 NM_005629.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007151
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.07

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-153694525-C-T is Benign according to our data. Variant chrX-153694525-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153694525-C-T is described in Lovd as [Benign]. Variant chrX-153694525-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000486 (54/111076) while in subpopulation EAS AF= 0.0117 (41/3513). AF 95% confidence interval is 0.00884. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.1496-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000253122.10
SLC6A8	NM_001142805.2	c.1466-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SLC6A8	NM_001142806.1	c.1151-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1496-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005629.4	P1
SLC6A8	ENST00000413787.1	c.425-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
SLC6A8	ENST00000430077.6	c.1151-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
SLC6A8	ENST00000485324.1	n.1795C>T		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.000468 AC: 52 AN: 111022 Hom.: 0 Cov.: 22 AF XY: 0.000512 AC XY: 17 AN XY: 33232

Gnomad AFR AF: 0.0000986

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0111

Gnomad SAS AF: 0.000380

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000114

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00104 AC: 190 AN: 182929 Hom.: 1 AF XY: 0.000974 AC XY: 66 AN XY: 67741

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0124

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000982

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000432 AC: 472 AN: 1093688 Hom.: 1 Cov.: 33 AF XY: 0.000428 AC XY: 154 AN XY: 359448

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.000204

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000486 AC: 54 AN: 111076 Hom.: 0 Cov.: 22 AF XY: 0.000541 AC XY: 18 AN XY: 33296

Gnomad4 AFR AF: 0.0000984

Gnomad4 AMR AF: 0.000283

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0117

Gnomad4 SAS AF: 0.000381

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000114

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000364 Hom.: 2

Bravo AF: 0.000544

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Creatine transporter deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2017

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 deficiency syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 24, 2019

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2018

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

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.24
Dann	Benign	0.40
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.11
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: rs376038235; hg19: chrX-152959980;