NM_005629.4:c.1208C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_005629.4(SLC6A8):​c.1208C>T​(p.Ala403Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 missense

Scores

10
6
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.80

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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005629.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
Variant X-153693971-C-T is Pathogenic according to our data. Variant chrX-153693971-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523485.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC6A8NM_005629.4 linkc.1208C>T p.Ala403Val missense_variant Exon 8 of 13 ENST00000253122.10 NP_005620.1 P48029-1X5D9C4
SLC6A8NM_001142805.2 linkc.1178C>T p.Ala393Val missense_variant Exon 8 of 13 NP_001136277.1 P48029Q59EV7
SLC6A8NM_001142806.1 linkc.863C>T p.Ala288Val missense_variant Exon 8 of 13 NP_001136278.1 P48029-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC6A8ENST00000253122.10 linkc.1208C>T p.Ala403Val missense_variant Exon 8 of 13 1 NM_005629.4 ENSP00000253122.5 P48029-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1064367
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
345973
African (AFR)
AF:
0.00
AC:
0
AN:
25691
American (AMR)
AF:
0.00
AC:
0
AN:
30100
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18818
East Asian (EAS)
AF:
0.00
AC:
0
AN:
28532
South Asian (SAS)
AF:
0.00
AC:
0
AN:
50827
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
37964
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3103
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
824544
Other (OTH)
AF:
0.00
AC:
0
AN:
44788
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Seizure;C0239234:Low-set ears;C0424503:Abnormal facial shape;C3714756:Intellectual disability Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.64
D;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Pathogenic
3.9
H;.
PhyloP100
7.8
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
0.74
P;.
Vest4
0.78
MutPred
0.72
Loss of glycosylation at P400 (P = 0.2724);.;
MVP
0.99
MPC
2.4
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.94
gMVP
0.97
Mutation Taster
=4/96
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1557045296; hg19: chrX-152959426; API