rs782040427

Positions:

chrX-153690395-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.283G>A variant in SLC6A8 is a missense variant predicted to cause a substitution of a valine by an isoleucine at amino acid position 95 (p.Val95Ile). This variant has not been reported in the published literature in individuals with creatine transporter deficiency. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00005 (4/78678 alleles, 2 hemizygotes) in the European (Non-Finnish) population, which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.644, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 449185, one-star review status), with conflicting interpretations of pathogenicity (one submitter: uncertain significance; two submitters: likely benign). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549177/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000017 ( 0 hom. 8 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -2.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC6A8	NM_005629.4 linkuse as main transcript	c.283G>A	p.Val95Ile	missense_variant	2/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 linkuse as main transcript	c.283G>A	p.Val95Ile	missense_variant	2/13		NP_001136277.1
SLC6A8	NM_001142806.1 linkuse as main transcript	c.-63G>A		5_prime_UTR_variant	2/13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.283G>A	p.Val95Ile	missense_variant	2/13	1	NM_005629.4	ENSP00000253122	P1	P48029-1
SLC6A8	ENST00000430077.6 linkuse as main transcript	c.-63G>A		5_prime_UTR_variant	2/13	2		ENSP00000403041		P48029-4
SLC6A8	ENST00000476466.1 linkuse as main transcript	n.135G>A		non_coding_transcript_exon_variant	2/3	3
SLC6A8	ENST00000675713.1 linkuse as main transcript	n.37G>A		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes

AF:

0.0000354

AC:

AN:

112846

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

35006

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000189

AC:

AN:

158720

Hom.:

AF XY:

0.0000201

AC XY:

AN XY:

49794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1086592

Hom.:

Cov.:

AF XY:

0.0000225

AC XY:

AN XY:

355054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000227

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000354

AC:

AN:

112846

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

35006

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2018

The V95I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V95I variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The V95I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Creatine transporter deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2018

This alteration is classified as likely 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

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.2

DANN

Benign

0.94

DEOGEN2

Benign

0.083

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.73

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.45

REVEL

Benign

0.070

Sift

Benign

0.23

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.072

MutPred

0.41

Loss of catalytic residue at V95 (P = 0.0665);

MVP

0.32

MPC

1.0

ClinPred

0.030

GERP RS

-1.1

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.068

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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