1-2029969-C-T

Variant names:

• chr1-2029969-C-T
• rs28431879
• NM_000815.5:c.1060-14C>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.1060-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,610,858 control chromosomes in the GnomAD database, including 21,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1836 hom., cov: 34)
  • Exomes 𝑓: 0.15 (19656 hom.)
• Consequence: GABRD NM_000815.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.951
• Publications: 5 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=-0.92).
• BP6: Variant 1-2029969-C-T is Benign according to our data. Variant chr1-2029969-C-T is described in ClinVar as [Benign]. Clinvar id is 256822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.1060-14C>T		intron_variant	Intron 8 of 8	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.1765-14C>T		intron_variant	Intron 7 of 7		XP_016856425.1
GABRD	XM_011541194.4	c.1099-14C>T		intron_variant	Intron 8 of 8		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.1060-14C>T		intron_variant	Intron 8 of 8	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19210 AN: 152204 Hom.: 1826 Cov.: 34

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.186 AC: 45833 AN: 246900 AF XY: 0.186

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.485

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.152 AC: 221246 AN: 1458536 Hom.: 19656 Cov.: 33 AF XY: 0.154 AC XY: 111574 AN XY: 725498

African (AFR) AF: 0.0299 AC: 1001 AN: 33436

American (AMR) AF: 0.230 AC: 10241 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2888 AN: 26052

East Asian (EAS) AF: 0.414 AC: 16421 AN: 39674

South Asian (SAS) AF: 0.239 AC: 20594 AN: 86040

European-Finnish (FIN) AF: 0.175 AC: 9113 AN: 52132

Middle Eastern (MID) AF: 0.102 AC: 586 AN: 5758

European-Non Finnish (NFE) AF: 0.136 AC: 150970 AN: 1110658

Other (OTH) AF: 0.156 AC: 9432 AN: 60282

GnomAD4 genome AF: 0.126 AC: 19237 AN: 152322 Hom.: 1836 Cov.: 34 AF XY: 0.132 AC XY: 9855 AN XY: 74484

African (AFR) AF: 0.0315 AC: 1310 AN: 41586

American (AMR) AF: 0.158 AC: 2424 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3472

East Asian (EAS) AF: 0.454 AC: 2347 AN: 5168

South Asian (SAS) AF: 0.260 AC: 1255 AN: 4832

European-Finnish (FIN) AF: 0.176 AC: 1873 AN: 10626

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9179 AN: 68010

Other (OTH) AF: 0.155 AC: 328 AN: 2116

Alfa AF: 0.107 Hom.: 347

Bravo AF: 0.124

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

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	-0.92
CADD	Benign	0.058
DANN	Benign	0.42
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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: rs28431879; hg19: chr1-1961408; COSMIC: COSV66079834; COSMIC: COSV66079834;