chrX-153693083-G-A

Position:

chrX-153693083-G-A

Variant summary

Our verdict is Uncertain significance. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.820G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 274 (p.Val274Met). This variant has been previously reported in one individual with hypotonia, global developmental delay, and microcephaly, but who was found to have normal urine creatine and guanidinoacetate levels on two separate occasions and a de novo variant in KAT6A as an alternate molecular cause of his symptoms (PMID 27133397) (BS2). In gnomAD v2.1.1, the highest population allele frequency is 0.00015 (14/91767 alleles) in the European (Non-Finnish) population and there are 4 hemizygotes across all populations, 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 0.559, 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: 4416002). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2.(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/CA10549333/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.000098 ( 0 hom. 33 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:3

Conservation

PhyloP100: 1.88

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 Uncertain_significance. Variant got -4 ACMG points.

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4 linkuse as main transcript	c.820G>A	p.Val274Met	missense_variant	5/13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 linkuse as main transcript	c.820G>A	p.Val274Met	missense_variant	5/13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 linkuse as main transcript	c.475G>A	p.Val159Met	missense_variant	5/13		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.820G>A	p.Val274Met	missense_variant	5/13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.0000532

AC:

AN:

112691

Hom.:

Cov.:

AF XY:

0.0000861

AC XY:

AN XY:

34851

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000930

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:

0.0000940

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000714

AC:

AN:

182136

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

67194

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:

0.0000527

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000148

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000976

AC:

107

AN:

1096467

Hom.:

Cov.:

AF XY:

0.0000911

AC XY:

AN XY:

362203

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:

0.000222

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000532

AC:

AN:

112691

Hom.:

Cov.:

AF XY:

0.0000861

AC XY:

AN XY:

34851

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000930

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000940

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Creatine transporter deficiency

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Nov 08, 2024	The NM_005629.4:c.820G>A variant in SLC6A8 is a missense variant predicted to cause the substitution of a valine by a methionine at amino acid position 274 (p.Val274Met). This variant has been previously reported in one individual with hypotonia, global developmental delay, and microcephaly, but who was found to have normal urine creatine and guanidinoacetate levels on two separate occasions and a de novo variant in KAT6A as an alternate molecular cause of his symptoms (PMID 27133397) (BS2). In gnomAD v2.1.1, the highest population allele frequency is 0.00015 (14/91767 alleles) in the European (Non-Finnish) population and there are 4 hemizygotes across all populations, 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 0.559, 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: 4416002). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS2. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) -

SLC6A8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;.

Vest4

0.39

MutPred

0.72

Loss of sheet (P = 0.0817);.;

MVP

0.85

MPC

2.2

ClinPred

0.22

GERP RS

4.9

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.27

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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