4-46250469-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000807.4(GABRA2):c.1195A>C(p.Lys399Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABRA2
• BP4: Computational evidence support a benign effect (MetaRNN=0.11122811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4	c.1195A>C	p.Lys399Gln	missense_variant	10/10	ENST00000381620.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA2	ENST00000381620.9	c.1195A>C	p.Lys399Gln	missense_variant	10/10	1	NM_000807.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250700 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135454

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 SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460484 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726576

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.1195A>C (p.K399Q) alteration is located in exon 9 (coding exon 9) of the GABRA2 gene. This alteration results from a A to C substitution at nucleotide position 1195, causing the lysine (K) at amino acid position 399 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Benign	0.86
DEOGEN2	Benign	0.12	T;T;T;T;T;T
Eigen	Benign	0.054
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.9	L;L;L;L;.;.
MutationTaster	Benign	0.60	N;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.31	N;N;N;N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.53	T;T;T;T;.;T
Sift4G	Benign	0.60	T;T;T;T;T;T
Polyphen		0.012	B;B;B;B;.;.
Vest4		0.11
MutPred		0.40		Loss of methylation at K399 (P = 0.0023);Loss of methylation at K399 (P = 0.0023);Loss of methylation at K399 (P = 0.0023);Loss of methylation at K399 (P = 0.0023);.;.;
MVP		0.78
MPC		0.28
ClinPred		0.18	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.43

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: rs747890495; hg19: chr4-46252486;