rs863225292

chr5-161895711-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001127644.2(GABRA1):c.902G>A(p.Arg301Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.88

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001127644.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 5-161895711-G-A is Pathogenic according to our data. Variant chr5-161895711-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217878.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA1	NM_001127644.2	c.902G>A	p.Arg301Lys	missense_variant	9/10	ENST00000393943.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA1	ENST00000393943.10	c.902G>A	p.Arg301Lys	missense_variant	9/10	1	NM_001127644.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 19 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mendelics

Aug 12, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;D;D;D;D;.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.5	M;M;M;M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
Polyphen		1.0	D;D;D;D;D;D;.;D;D
Vest4		0.72, 0.74, 0.73, 0.73
MutPred		0.83		Gain of ubiquitination at R301 (P = 0.0258);Gain of ubiquitination at R301 (P = 0.0258);Gain of ubiquitination at R301 (P = 0.0258);Gain of ubiquitination at R301 (P = 0.0258);Gain of ubiquitination at R301 (P = 0.0258);Gain of ubiquitination at R301 (P = 0.0258);.;Gain of ubiquitination at R301 (P = 0.0258);Gain of ubiquitination at R301 (P = 0.0258);
MVP		0.97
MPC		3.3
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.97

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: rs863225292; hg19: chr5-161322717;