Genetic Variant NM_000807.4:c.396A>T (chr4-46312576-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000807.4(GABRA2):c.396A>T(p.Lys132Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K132E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GABRA2
NM_000807.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.110

Publications

123 publications found

Variant links:

Genes affected

GABRA2 (HGNC:4076): (gamma-aminobutyric acid type A receptor subunit alpha2) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

GABRA2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 78
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000807.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRA2	NM_000807.4	MANE Select	c.396A>T	p.Lys132Asn	missense	Exon 5 of 10	NP_000798.2
GABRA2	NM_001330690.2		c.396A>T	p.Lys132Asn	missense	Exon 5 of 11	NP_001317619.1
GABRA2	NM_001377144.1		c.396A>T	p.Lys132Asn	missense	Exon 5 of 11	NP_001364073.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.396A>T	p.Lys132Asn	missense	Exon 5 of 10	ENSP00000371033.4
GABRA2	ENST00000515082.5	TSL:1	c.396A>T	p.Lys132Asn	missense	Exon 5 of 9	ENSP00000423840.1
GABRA2	ENST00000507069.5	TSL:3	c.396A>T	p.Lys132Asn	missense	Exon 4 of 10	ENSP00000427603.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Benign

-0.054

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.69

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.3

PhyloP100

-0.11

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.81

MutPred

0.63

Loss of methylation at K132 (P = 0.0083)

MVP

0.94

MPC

3.0

ClinPred

1.0

GERP RS

-6.0

Varity_R

0.88

gMVP

0.96

Mutation Taster

=15/85

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over