4-46250318-A-G

Position:

• chr4-46250318-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The ENST00000381620.9(GABRA2):​c.1346T>C​(p.Val449Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,936 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GABRA2 ENST00000381620.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.15

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRA2. . Gene score misZ 3.1277 (greater than the threshold 3.09). Trascript score misZ 3.4041 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 78, undetermined early-onset epileptic encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08097023).
• BP6: Variant 4-46250318-A-G is Benign according to our data. Variant chr4-46250318-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1349771.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.1346T>C	p.Val449Ala	missense_variant	10/10	ENST00000381620.9	NP_000798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9	c.1346T>C	p.Val449Ala	missense_variant	10/10	1	NM_000807.4	ENSP00000371033	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456936 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724742

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.083	T;T;T;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;.;.;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.081	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.41	N;N;N;N;.;.
MutationTaster	Benign	0.96	N;N;N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.49	N;N;N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.16	T;T;T;T;.;T
Sift4G	Benign	0.61	T;T;T;T;T;T
Polyphen		0.0020	B;B;B;B;.;.
Vest4		0.028
MutPred		0.20		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;.;
MVP		0.41
MPC		0.29
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.059
gMVP		0.28

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: chr4-46252335;