Genetic Variant SLC6A1:p.Ser18Cys (chr3-11017263-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003042.4(SLC6A1):c.52A>T(p.Ser18Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S18G) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.99

Publications

0 publications found

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]

SLC6A1 links:

SLC6A1-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

SLC6A1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36142075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4 link	c.52A>T	p.Ser18Cys	missense_variant	Exon 3 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10 link	c.52A>T	p.Ser18Cys	missense_variant	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

0.0040

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.36

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.69

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;.;.;.

PhyloP100

8.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.029

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.066

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.95

P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;.;P;P;.;.;.

Vest4

0.23

MutPred

0.30

Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);

MVP

0.65

MPC

1.7

ClinPred

0.85

GERP RS

4.4

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.11

gMVP

0.48

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over