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GeneBe

rs6344

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003042.4(SLC6A1):c.651G>A(p.Thr217=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,456 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T217T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0032 ( 14 hom. )

Consequence

SLC6A1
NM_003042.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.33
Variant links:
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 Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 3-11022405-G-A is Benign according to our data. Variant chr3-11022405-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-11022405-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.33 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (346/152330) while in subpopulation NFE AF= 0.0039 (265/68026). AF 95% confidence interval is 0.00351. There are 2 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd at 346 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A1NM_003042.4 linkuse as main transcriptc.651G>A p.Thr217= synonymous_variant 7/16 ENST00000287766.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A1ENST00000287766.10 linkuse as main transcriptc.651G>A p.Thr217= synonymous_variant 7/161 NM_003042.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00227
AC:
346
AN:
152212
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00353
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00390
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00201
AC:
502
AN:
249628
Hom.:
0
AF XY:
0.00211
AC XY:
284
AN XY:
134884
show subpopulations
Gnomad AFR exome
AF:
0.000559
Gnomad AMR exome
AF:
0.00105
Gnomad ASJ exome
AF:
0.0000995
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000428
Gnomad FIN exome
AF:
0.000651
Gnomad NFE exome
AF:
0.00363
Gnomad OTH exome
AF:
0.00328
GnomAD4 exome
AF:
0.00317
AC:
4630
AN:
1461126
Hom.:
14
Cov.:
31
AF XY:
0.00308
AC XY:
2239
AN XY:
726776
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00148
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000383
Gnomad4 FIN exome
AF:
0.000356
Gnomad4 NFE exome
AF:
0.00389
Gnomad4 OTH exome
AF:
0.00275
GnomAD4 genome
AF:
0.00227
AC:
346
AN:
152330
Hom.:
2
Cov.:
33
AF XY:
0.00192
AC XY:
143
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.00353
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00390
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000146
Hom.:
176
Bravo
AF:
0.00250

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023SLC6A1: BP4, BP7, BS1 -
Benign, criteria provided, single submitterclinical testingGeneDxNov 08, 2019- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
SLC6A1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 22, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 15, 2016This alteration is classified as likely 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. -
Myoclonic-atonic epilepsy Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
Cadd
Benign
9.9
Dann
Benign
0.85

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

LitVar

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

Other links and lift over

dbSNP: rs6344; hg19: chr3-11064091; API