Variant 3-10819744-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014229.3(SLC6A11):c.424C>T(p.His142Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H142L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLC6A11
NM_014229.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Variant links:

Genes affected

SLC6A11 (HGNC:11044): (solute carrier family 6 member 11) The protein encoded by this gene is a sodium-dependent transporter that uptakes gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, which ends the GABA neurotransmission. Defects in this gene may result in epilepsy, behavioral problems, or intellectual problems. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

SLC6A11 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06377053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC6A11	NM_014229.3 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	3/14	ENST00000254488.7
SLC6A11	NM_001317406.3 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	3/4
SLC6A11	XM_011534033.3 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A11	ENST00000254488.7 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	3/14	1	NM_014229.3	P1	P48066-1
SLC6A11	ENST00000454147.1 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	3/4	1			P48066-2

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251434

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000133

AC:

195

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.424C>T (p.H142Y) alteration is located in exon 3 (coding exon 3) of the SLC6A11 gene. This alteration results from a C to T substitution at nucleotide position 424, causing the histidine (H) at amino acid position 142 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.1

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.36

MVP

0.53

MPC

0.73

ClinPred

0.033

GERP RS

4.4

Varity_R

0.17

gMVP

0.67

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over