rs1064795099
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_003042.4(SLC6A1):c.1377C>A(p.Ser459Arg) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
SLC6A1
NM_003042.4 missense
NM_003042.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 1.52
Genes affected
SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the SLC6A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 4.1766 (above the threshold of 3.09). Trascript score misZ: 4.9229 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
PP5
Variant 3-11031230-C-A is Pathogenic according to our data. Variant chr3-11031230-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421382.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC6A1 | NM_003042.4 | c.1377C>A | p.Ser459Arg | missense_variant | Exon 13 of 16 | ENST00000287766.10 | NP_003033.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Jul 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
May 10, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32277047) -
Epilepsy with myoclonic atonic seizures Pathogenic:1
Jun 01, 2022
Solve-RD Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation
Variant confirmed as disease-causing by referring clinical team -
Marfanoid habitus and intellectual disability Pathogenic:1
-
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;D;.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H;H;H;.;H;.;H;H;H;H;.;H;H;H;.;H;H;H;.;H;H;H;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Vest4
0.85
MutPred
Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;
MVP
0.95
MPC
1.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at