rs782028471

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.537

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 Likely_benign. Variant got -2 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC6A8	NM_005629.4 linkuse as main transcript	c.1627G>A	p.Glu543Lys	missense_variant	12/13	ENST00000253122.10
SLC6A8	NM_001142805.2 linkuse as main transcript	c.1597G>A	p.Glu533Lys	missense_variant	12/13
SLC6A8	NM_001142806.1 linkuse as main transcript	c.1282G>A	p.Glu428Lys	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.1627G>A	p.Glu543Lys	missense_variant	12/13	1	NM_005629.4	P1	P48029-1
SLC6A8	ENST00000430077.6 linkuse as main transcript	c.1282G>A	p.Glu428Lys	missense_variant	12/13	2			P48029-4
SLC6A8	ENST00000485324.1 linkuse as main transcript	n.1934G>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112486

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34678

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

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182609

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67637

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000333

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112486

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34678

show subpopulations

Gnomad4 AFR

AF:

0.0000323

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:

0.0000188

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 23, 2015

- -

Creatine transporter deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

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

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;.

MutationTaster

Benign

0.87

D;D

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

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

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