3-11020234-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_003042.4(SLC6A1):c.493G>T(p.Asp165Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,306 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. D165N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.65

Publications

3 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 Gene-Disease associations (from GenCC):

epilepsy with myoclonic atonic seizures
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

SLC6A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_003042.4

BP4

Computational evidence support a benign effect (MetaRNN=0.3184967).

BS2

High AC in GnomAd4 at 9 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4 link	c.493G>T	p.Asp165Tyr	missense_variant	Exon 6 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.493G>T	p.Asp165Tyr	missense_variant	Exon 6 of 16	1	NM_003042.4	ENSP00000287766.4		P30531

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000999

AC:

AN:

250356

AF XY:

0.0000887

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00103

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461110

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86058

European-Finnish (FIN)

AF:

0.000676

AC:

AN:

53228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111722

Other (OTH)

AF:

0.0000331

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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

AF:

0.0000591

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000741

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

0.0013

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

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

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.32

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

Uncertain

0.16

MutationAssessor

Uncertain

2.6

M;M;M;.;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;M;M;M;.;.

PhyloP100

3.6

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.63

Sift

Benign

0.046

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

Sift4G

Benign

0.070

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

Polyphen

0.98

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

Vest4

0.40

MutPred

0.54

Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);.;Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);.;Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);.;Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);Loss of ubiquitination at K162 (P = 0.1741);

MVP

0.79

MPC

2.1

ClinPred

0.83

GERP RS

3.3

Varity_R

0.59

gMVP

0.81

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over