rs782028471

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005629.4(SLC6A8):c.1627G>A(p.Glu543Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,209,700 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E543Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000028 ( 0 hom. 11 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.537

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

creatine transporter deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.089541465).

BP6

Variant X-153694749-G-A is Benign according to our data. Variant chrX-153694749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212212.

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1627G>A	p.Glu543Lys	missense_variant	Exon 12 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1597G>A	p.Glu533Lys	missense_variant	Exon 12 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1282G>A	p.Glu428Lys	missense_variant	Exon 12 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.1627G>A	p.Glu543Lys	missense_variant	Exon 12 of 13	1	NM_005629.4	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000430077.6 link	c.1282G>A	p.Glu428Lys	missense_variant	Exon 12 of 13	2		ENSP00000403041.2	P48029-4
SLC6A8	ENST00000485324.1 link	n.1934G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2
SLC6A8	ENST00000413787.1 link	c.*173G>A		downstream_gene_variant		5		ENSP00000400463.1	H7C1I2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182609

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000724

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1097214

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

362958

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26374

American (AMR)

AF:

0.0000284

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54097

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3644

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

841902

Other (OTH)

AF:

0.0000217

AC:

AN:

46028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112486

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34678

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30998

American (AMR)

AF:

0.00

AC:

AN:

10735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2757

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53159

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 23, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Creatine transporter deficiency

Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 543 of the SLC6A8 protein (p.Glu543Lys). This variant is present in population databases (rs782028471, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. ClinVar contains an entry for this variant (Variation ID: 212212). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Creatine deficiency syndrome 1

Uncertain:1

Nov 11, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 02, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.054

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.010

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.083

T;.

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.81

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.090

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;.

PhyloP100

0.54

PrimateAI

Benign

0.39

PROVEAN

Benign

0.70

N;N

REVEL

Benign

0.15

Sift

Benign

0.63

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0020

B;.

Vest4

0.23

MVP

0.28

MPC

0.17

ClinPred

0.016

GERP RS

-6.8

Varity_R

0.067

gMVP

0.71

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over