4-46250395-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000807.4(GABRA2):c.1269A>G(p.Ile423Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4	c.1269A>G	p.Ile423Met	missense_variant	10/10	ENST00000381620.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA2	ENST00000381620.9	c.1269A>G	p.Ile423Met	missense_variant	10/10	1	NM_000807.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459954 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 29, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 483 of the GABRA2 protein (p.Ile483Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GABRA2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;T;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.9	M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N;N;N;N;.;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.84
MutPred		0.65		Gain of glycosylation at S421 (P = 0.0323);Gain of glycosylation at S421 (P = 0.0323);Gain of glycosylation at S421 (P = 0.0323);Gain of glycosylation at S421 (P = 0.0323);.;.;
MVP		0.86
MPC		0.87
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.43
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-46252412;