rs994082959

Variant names:

• chr1-2019501-C-A
• rs994082959
• NM_000815.5:c.68+10C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-2019501-C-A
• chr1-2019501-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_000815.5(GABRD):​c.68+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 307,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GABRD NM_000815.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.68+10C>A		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+10C>A		intron_variant	Intron 1 of 8	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.0000162 AC: 5 AN: 307938 Hom.: 0 Cov.: 0 AF XY: 0.0000206 AC XY: 3 AN XY: 145700

African (AFR) AF: 0.00 AC: 0 AN: 6360

American (AMR) AF: 0.00 AC: 0 AN: 1948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3770

East Asian (EAS) AF: 0.00 AC: 0 AN: 7480

South Asian (SAS) AF: 0.00 AC: 0 AN: 5660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 828

European-Non Finnish (NFE) AF: 0.0000190 AC: 5 AN: 263840

Other (OTH) AF: 0.00 AC: 0 AN: 12144

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.55
PhyloP100		0.10
PromoterAI		0.034	Neutral

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

Other links and lift over

dbSNP: rs994082959; hg19: chr1-1950940;