rs200353790

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP7

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549215/MONDO:0010305/027

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

Scores

Clinical Significance

Likely benign reviewed by expert panel B:2

Conservation

PhyloP100: -0.0680

Variant links:

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]

SLC6A8 links:

SLC6A8 (HGNC:):

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
SLC6A8	NM_005629.4 linkuse as main transcript	c.644+9G>A	intron_variant	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 linkuse as main transcript	c.644+9G>A	intron_variant		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 linkuse as main transcript	c.299+9G>A	intron_variant		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.644+9G>A		intron_variant		1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.0000353

AC:

AN:

113309

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

35461

show subpopulations

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:

AN:

180354

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66200

show subpopulations

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:

AN:

1096557

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362545

show subpopulations

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:

AN:

113309

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

35461

show subpopulations

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.:

Bravo

AF:

0.0000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Benign:2

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). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over