4-46250444-GC-TT

Position:

• chr4-46250444-GC-TT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_000807.4(GABRA2):​c.1219_1220delinsAA​(p.Ala407Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA2 NM_000807.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.13

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 2 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.
• BP6: Variant 4-46250444-GC-TT is Benign according to our data. Variant chr4-46250444-GC-TT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA2	NM_000807.4	c.1219_1220delinsAA	p.Ala407Lys	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.1219_1220delinsAA	p.Ala407Lys	missense_variant	10/10	1	NM_000807.4	ENSP00000371033	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2017

The c.1219_1220delGCinsAA variant in the GABRA2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1219_1220delGCinsAA variant results in the replacement of the normal Alanine at position 407 with a Lysine residue, denoted p.Ala407Lys. The c.1219_1220delGCinsAA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1219_1220delGCinsAA variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.1219_1220delGCinsAA as a variant of uncertain significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553895447; hg19: chr4-46252461;