4-46250450-G-A

Position:

• chr4-46250450-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000807.4(GABRA2):​c.1214C>T​(p.Ala405Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.81

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 -6 ACMG points.

• 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=0.1110695).
• BP6: Variant 4-46250450-G-A is Benign according to our data. Variant chr4-46250450-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2630020.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4	c.1214C>T	p.Ala405Val	missense_variant	10/10	ENST00000381620.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA2	ENST00000381620.9	c.1214C>T	p.Ala405Val	missense_variant	10/10	1	NM_000807.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151594 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460324 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726504

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151594 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73984

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

GABRA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

The GABRA2 c.1214C>T variant is predicted to result in the amino acid substitution p.Ala405Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.77
DEOGEN2	Benign	0.13	T;T;T;T;T;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	.;.;.;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.90	L;L;L;L;.;.
MutationTaster	Benign	0.79	N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	N;N;N;N;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.52	T;T;T;T;.;D
Sift4G	Benign	0.32	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.;.
Vest4		0.11
MutPred		0.50		Gain of glycosylation at T410 (P = 0.0298);Gain of glycosylation at T410 (P = 0.0298);Gain of glycosylation at T410 (P = 0.0298);Gain of glycosylation at T410 (P = 0.0298);.;.;
MVP		0.62
MPC		0.24
ClinPred		0.18	T
GERP RS		6.0
Varity_R		0.085
gMVP		0.25

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: rs1187844488; hg19: chr4-46252467;