5-161873196-G-T

Variant names:

• chr5-161873196-G-T
• NM_001127644.2:c.335G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_001127644.2(GABRA1):​c.335G>T​(p.Arg112Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R112Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-161873196-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the GABRA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.1498 (above the threshold of 3.09). Trascript score misZ: 4.2662 (above the threshold of 3.09). GenCC associations: The gene is linked to juvenile myoclonic epilepsy, developmental and epileptic encephalopathy, 19, epilepsy, idiopathic generalized, susceptibility to, 13, Dravet syndrome, developmental and epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.335G>T	p.Arg112Leu	missense_variant	Exon 5 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.335G>T	p.Arg112Leu	missense_variant	Exon 5 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 Uncertain:1

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with GABRA1-related conditions. 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. This variant disrupts the p.Arg112 amino acid residue in GABRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24623842, 26918889, 27521439). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 112 of the GABRA1 protein (p.Arg112Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;D;D;D;T;D;.;D;.;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;D;.;D;.;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	L;L;L;L;L;.;L;.;L;.;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	.;D;D;D;D;D;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Benign	0.065	.;T;T;T;T;D;.;.;.;.;.
Sift4G	Benign	0.31	.;T;T;T;T;T;.;.;.;T;.
Polyphen		0.31	B;B;B;B;B;.;B;.;B;.;B
Vest4		0.78, 0.73
MutPred		0.60		Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);.;Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);
MVP		0.96
MPC		1.4
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.96

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: chr5-161300202;