chrX-153695096-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005629.4(SLC6A8):​c.1790C>T​(p.Pro597Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P597P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

SLC6A8
NM_005629.4 missense

Scores

9
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.81
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A8NM_005629.4 linkuse as main transcriptc.1790C>T p.Pro597Leu missense_variant 13/13 ENST00000253122.10
SLC6A8NM_001142805.2 linkuse as main transcriptc.1760C>T p.Pro587Leu missense_variant 13/13
SLC6A8NM_001142806.1 linkuse as main transcriptc.1445C>T p.Pro482Leu missense_variant 13/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A8ENST00000253122.10 linkuse as main transcriptc.1790C>T p.Pro597Leu missense_variant 13/131 NM_005629.4 P1P48029-1
SLC6A8ENST00000430077.6 linkuse as main transcriptc.1445C>T p.Pro482Leu missense_variant 13/132 P48029-4
SLC6A8ENST00000485324.1 linkuse as main transcriptn.2097C>T non_coding_transcript_exon_variant 6/62

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Creatine transporter deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 20, 2019In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SLC6A8-related disease. This sequence change replaces proline with leucine at codon 597 of the SLC6A8 protein (p.Pro597Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Uncertain
0.70
D;D
MetaSVM
Uncertain
0.046
D
MutationAssessor
Benign
0.81
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.4
D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.50
MutPred
0.67
Gain of MoRF binding (P = 0.0648);.;
MVP
0.84
MPC
0.66
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.68
gMVP
0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060502811; hg19: chrX-152960551; API