1-2019496-G-A

Variant names:

• chr1-2019496-G-A
• rs1571022283
• NM_000815.5:c.68+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000815.5(GABRD):​c.68+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000104 in 964,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GABRD NM_000815.5 splice_region, intron
• Scores: Splicing: ADA: 0.9979
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.68+5G>A		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000378585.7	NP_000806.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.68+5G>A		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000104 AC: 1 AN: 964096 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 452750

African (AFR) AF: 0.00 AC: 0 AN: 19000

American (AMR) AF: 0.00 AC: 0 AN: 4740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9432

East Asian (EAS) AF: 0.00 AC: 0 AN: 14890

South Asian (SAS) AF: 0.00 AC: 0 AN: 18238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2292

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 846258

Other (OTH) AF: 0.00 AC: 0 AN: 35454

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.88
PhyloP100		2.2
PromoterAI		-0.12	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
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: rs1571022283; hg19: chr1-1950935;