4-46250330-G-T

Variant names:

• chr4-46250330-G-T
• rs761715134
• NM_000807.4:c.1334C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000807.4(GABRA2):​c.1334C>A​(p.Pro445His) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,458,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P445S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.86

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36968914).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.1334C>A	p.Pro445His	missense_variant	Exon 10 of 10	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.1334C>A	p.Pro445His	missense_variant	Exon 10 of 10	1	NM_000807.4	ENSP00000371033.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249054 AF XY: 0.0000148

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: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458862 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725802

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33222

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44424

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25970

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39630

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86156

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53316

Gnomad4 NFE exome AF: 0.00000631 AC: 7 AN: 1110214

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60190

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 505 of the GABRA2 protein (p.Pro505His). This variant is present in population databases (rs761715134, gnomAD 0.003%). 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	0.25
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;.;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	2.0	M;M;M;M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.6	D;D;D;D;.;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.53
MutPred		0.32		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);.;.;
MVP		0.68
MPC		0.91
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.54
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs761715134; hg19: chr4-46252347;