rs200353790

chrX-153691562-G-AchrX-153691562-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005629.4(SLC6A8):c.644+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,209,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 0.000035 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000046 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 intron
• Clinical Significance: Likely benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.0680

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-153691562-G-A is Benign according to our data. Variant chrX-153691562-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416004.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-153691562-G-A is described in Lovd as [Likely_benign].
• 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.644+9G>A		intron_variant		ENST00000253122.10
SLC6A8	NM_001142805.2	c.644+9G>A		intron_variant
SLC6A8	NM_001142806.1	c.299+9G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.644+9G>A		intron_variant		1	NM_005629.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000353 AC: 4 AN: 113309 Hom.: 0 Cov.: 24 AF XY: 0.0000564 AC XY: 2 AN XY: 35461

Gnomad AFR AF: 0.0000320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000184

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000333 AC: 6 AN: 180354 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66200

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000660

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096557 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362545

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.0000353 AC: 4 AN: 113309 Hom.: 0 Cov.: 24 AF XY: 0.0000564 AC XY: 2 AN XY: 35461

Gnomad4 AFR AF: 0.0000320

Gnomad4 AMR AF: 0.000184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	- -
Likely benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jan 12, 2023	The NM_005629.4:c.644+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 3. This variant was reported in a female patient with intellectual disability (LOVD, https://databases.lovd.nl/shared/genes/SLC6A8; individual #00185850) but details of biochemical testing or brain MRS are not available (PMID: 20717164). The computational splicing predictors SpliceAI and varSEAK suggest that the variant has no impact on splicing (BP4). This is also supported by the reported results of 5 different predictors (Netgene2, Fruitfly (i.e. NNSplice), Splice predictor, Genscan W, FSplice) (PMID 20717164). PhyloP100 way score for this intronic variant is 0.35, which is below the threshols of 2.0, indicating that this nucleotide is not highly conserved (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001061 in the African population. This allele frequency is between the ClinGen CCDS VCEP’s allele frequency thresholds for PM2 (<0.00002) and BS1 (>0.0002). Therefore, neither code is met. There is a ClinVar entry for this variant (Variation ID: 416004) In summary, this variant meets the criteria to be classified as likely benign for X-linked creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications verion 1.1.0): BP4. BP7. This classification was approved by the ClinGen CCDS VCEP on Jan 12, 2023). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.6
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs200353790; hg19: chrX-152957017; COSMIC: COSV53471472; COSMIC: COSV53471472;