NM_005629.4:c.1516G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005629.4(SLC6A8):c.1516G>A(p.Asp506Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,207,138 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 151 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D506G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00038 ( 0 hom. 143 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.44

Publications

0 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022884935).

BP6

Variant X-153694553-G-A is Benign according to our data. Variant chrX-153694553-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1516G>A	p.Asp506Asn	missense_variant	Exon 11 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1486G>A	p.Asp496Asn	missense_variant	Exon 11 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1171G>A	p.Asp391Asn	missense_variant	Exon 11 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.1516G>A	p.Asp506Asn	missense_variant	Exon 11 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

AF:

0.000363

AC:

AN:

110228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000994

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00380

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000494

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000459

AC:

AN:

183109

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00240

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.000750

Gnomad NFE exome

AF:

0.000625

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000383

AC:

420

AN:

1096910

Hom.:

Cov.:

AF XY:

0.000395

AC XY:

143

AN XY:

362434

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26365

American (AMR)

AF:

0.0000284

AC:

AN:

35188

Ashkenazi Jewish (ASJ)

AF:

0.00258

AC:

AN:

19375

East Asian (EAS)

AF:

0.0000994

AC:

AN:

30195

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54120

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

40455

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.000385

AC:

324

AN:

841083

Other (OTH)

AF:

0.000326

AC:

AN:

46035

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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

100

<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:

0.000363

AC:

AN:

110228

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

AN XY:

32502

show subpopulations

African (AFR)

AF:

0.0000994

AC:

AN:

30174

American (AMR)

AF:

0.00

AC:

AN:

10450

Ashkenazi Jewish (ASJ)

AF:

0.00380

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3471

South Asian (SAS)

AF:

0.00

AC:

AN:

2564

European-Finnish (FIN)

AF:

0.000170

AC:

AN:

5898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.000494

AC:

AN:

52635

Other (OTH)

AF:

0.00

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000482

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 19, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Creatine transporter deficiency

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 31, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

not provided

Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC6A8: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.16

T;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

1.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.70

N;N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.048

B;.;.

Vest4

0.24

MVP

0.60

MPC

0.36

ClinPred

0.030

GERP RS

4.8

Varity_R

0.19

gMVP

0.97

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over