Genetic Variant SLC6A8:p.Asp505Glu (chrX-153694552-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005629.4(SLC6A8):c.1515C>A(p.Asp505Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 110,276 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D505D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.75

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23056585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC6A8	NM_005629.4 link	c.1515C>A	p.Asp505Glu	missense_variant	Exon 11 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 link	c.1485C>A	p.Asp495Glu	missense_variant	Exon 11 of 13		NP_001136277.1
SLC6A8	NM_001142806.1 link	c.1170C>A	p.Asp390Glu	missense_variant	Exon 11 of 13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.1515C>A	p.Asp505Glu	missense_variant	Exon 11 of 13	1	NM_005629.4	ENSP00000253122.5

Frequencies

GnomAD3 genomes

AF:

0.00000907

AC:

AN:

110276

Hom.:

Cov.:

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000907

AC:

AN:

110276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32530

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30152

American (AMR)

AF:

0.00

AC:

AN:

10455

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3490

South Asian (SAS)

AF:

0.00

AC:

AN:

2586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52667

Other (OTH)

AF:

0.00

AC:

AN:

1491

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.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.070

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.42

T;.;.

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

-5.8

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Uncertain

0.29

Sift

Benign

0.048

D;T;T

Sift4G

Benign

0.10

T;T;D

Polyphen

0.81

P;.;.

Vest4

0.19

MutPred

0.45

Loss of stability (P = 0.3484);.;.;

MVP

0.60

MPC

0.53

ClinPred

0.49

GERP RS

-8.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.84

Mutation Taster

=49/51

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over