rs2376805

Variant names:

• chr1-2024923-G-A
• rs2376805
• NM_000815.5:c.69-19G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-2024923-G-A
• chr1-2024923-G-C
• chr1-2024923-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000815.5(GABRD):​c.69-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,568,616 control chromosomes in the GnomAD database, including 528,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50323 hom., cov: 36)
  • Exomes 𝑓: 0.82 (477942 hom.)
• Consequence: GABRD NM_000815.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.221
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-2024923-G-A is Benign according to our data. Variant chr1-2024923-G-A is described in ClinVar as Benign. ClinVar VariationId is 256824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.69-19G>A		intron_variant	Intron 1 of 8	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.755G>A	p.Arg252Gln	missense_variant	Exon 1 of 8		XP_016856425.1
GABRD	XM_011541194.4	c.108-19G>A		intron_variant	Intron 1 of 8		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.69-19G>A		intron_variant	Intron 1 of 8	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123660 AN: 152152 Hom.: 50293 Cov.: 36

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.827

GnomAD2 exomes AF: 0.803 AC: 200186 AN: 249240 AF XY: 0.807

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 0.717

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.831

Gnomad OTH exome AF: 0.824

GnomAD4 exome AF: 0.821 AC: 1162309 AN: 1416348 Hom.: 477942 Cov.: 23 AF XY: 0.820 AC XY: 579931 AN XY: 707314

African (AFR) AF: 0.800 AC: 26058 AN: 32554

American (AMR) AF: 0.744 AC: 33141 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 22841 AN: 25764

East Asian (EAS) AF: 0.727 AC: 28690 AN: 39438

South Asian (SAS) AF: 0.770 AC: 65594 AN: 85166

European-Finnish (FIN) AF: 0.843 AC: 44090 AN: 52304

Middle Eastern (MID) AF: 0.843 AC: 4792 AN: 5684

European-Non Finnish (NFE) AF: 0.829 AC: 888664 AN: 1072020

Other (OTH) AF: 0.823 AC: 48439 AN: 58862

GnomAD4 genome AF: 0.813 AC: 123740 AN: 152268 Hom.: 50323 Cov.: 36 AF XY: 0.811 AC XY: 60364 AN XY: 74452

African (AFR) AF: 0.795 AC: 33027 AN: 41542

American (AMR) AF: 0.767 AC: 11740 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3139 AN: 3472

East Asian (EAS) AF: 0.720 AC: 3730 AN: 5182

South Asian (SAS) AF: 0.780 AC: 3771 AN: 4834

European-Finnish (FIN) AF: 0.847 AC: 9002 AN: 10622

Middle Eastern (MID) AF: 0.884 AC: 258 AN: 292

European-Non Finnish (NFE) AF: 0.830 AC: 56472 AN: 68002

Other (OTH) AF: 0.828 AC: 1751 AN: 2114

Alfa AF: 0.829 Hom.: 9602

Bravo AF: 0.808

Asia WGS AF: 0.755 AC: 2631 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epilepsy, idiopathic generalized, susceptibility to, 10 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Idiopathic generalized epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.25
PhyloP100		-0.22
PromoterAI		0.00060	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2376805; hg19: chr1-1956362; COSMIC: COSV66080160; COSMIC: COSV66080160;