1-2030097-A-G

Variant names:

• chr1-2030097-A-G
• rs1553123940
• NM_000815.5:c.1174A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000815.5(GABRD):​c.1174A>G​(p.Arg392Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.365
• Publications: 0 publications found

Genes affected

GABRD (HGNC:4084): (gamma-aminobutyric acid type A receptor subunit delta) Gamma-aminobutyric acid (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. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

GABRD Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 10

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0743967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.1174A>G	p.Arg392Gly	missense_variant	Exon 9 of 9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.1879A>G	p.Arg627Gly	missense_variant	Exon 8 of 8		XP_016856425.1
GABRD	XM_011541194.4	c.1213A>G	p.Arg405Gly	missense_variant	Exon 9 of 9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.1174A>G	p.Arg392Gly	missense_variant	Exon 9 of 9	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445336 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717678

African (AFR) AF: 0.00 AC: 0 AN: 32980

American (AMR) AF: 0.00 AC: 0 AN: 42426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25252

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 84250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103902

Other (OTH) AF: 0.00 AC: 0 AN: 59618

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy Uncertain:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 392 of the GABRD protein (p.Arg392Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GABRD-related conditions. ClinVar contains an entry for this variant (Variation ID: 529510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.074	T
PhyloP100		0.36
ClinPred		0.096	T
GERP RS		1.3
Varity_R		0.10
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553123940; hg19: chr1-1961536;