Genetic Variant SLC6A1:p.Gly11Arg (chr3-11017242-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003042.4(SLC6A1):c.31G>C(p.Gly11Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.40

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4 link	c.31G>C	p.Gly11Arg	missense_variant	Exon 3 of 16	ENST00000287766.10	NP_003033.3	A0A024R2K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10 link	c.31G>C	p.Gly11Arg	missense_variant	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4		P30531

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727188

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:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.27

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.49

T;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

-0.54

MutationAssessor

Benign

0.97

L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;.;L;L;.;.;.

PhyloP100

9.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.46

Sift

Benign

0.17

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

Sift4G

Benign

0.16

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

Polyphen

1.0

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

Vest4

0.69

MutPred

0.22

Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);

MVP

0.83

MPC

2.1

ClinPred

0.97

GERP RS

4.4

PromoterAI

0.011

Neutral

(source)

Varity_R

0.19

gMVP

0.87

Mutation Taster

=199/101

polymorphism

(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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3-11017242-G-C

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