Genetic Variant NM_005629.4:c.1713C>G (chrX-153694835-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005629.4(SLC6A8):c.1713C>G(p.Cys571Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 113,004 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. C571R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 25)

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.148

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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	NM_005629.4	MANE Select	c.1713C>G	p.Cys571Trp	missense	Exon 12 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.1683C>G	p.Cys561Trp	missense	Exon 12 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.1368C>G	p.Cys456Trp	missense	Exon 12 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1713C>G	p.Cys571Trp	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.1710C>G	p.Cys570Trp	missense	Exon 12 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.1704C>G	p.Cys568Trp	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

113004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000321

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000885

AC:

AN:

113004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35158

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31152

American (AMR)

AF:

0.00

AC:

AN:

10795

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3585

South Asian (SAS)

AF:

0.00

AC:

AN:

2816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6273

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53277

Other (OTH)

AF:

0.00

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

8.3

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.49

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.5

PhyloP100

-0.15

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.48

Sift

Benign

0.055

Sift4G

Benign

0.22

Polyphen

0.018

Vest4

0.85

MutPred

0.83

Loss of helix (P = 0.0558)

MVP

0.97

MPC

0.76

ClinPred

0.75

GERP RS

-0.081

Varity_R

0.74

gMVP

0.97

Mutation Taster

=44/56

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over