rs77892827

chr1-2025682-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000815.5(GABRD):c.414G>A(p.Thr138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 1,613,010 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: GABRD NM_000815.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.92

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005391568).
• BP6: Variant 1-2025682-G-A is Benign according to our data. Variant chr1-2025682-G-A is described in ClinVar as [Benign]. Clinvar id is 460010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00055 (803/1460620) while in subpopulation AFR AF= 0.0165 (553/33478). AF 95% confidence interval is 0.0154. There are 7 homozygotes in gnomad4_exome. There are 372 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRD	NM_000815.5	c.414G>A	p.Thr138=	synonymous_variant	4/9	ENST00000378585.7
GABRD	XM_017000936.2	c.1119G>A	p.Thr373=	synonymous_variant	3/8
GABRD	XM_011541194.4	c.453G>A	p.Thr151=	synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRD	ENST00000378585.7	c.414G>A	p.Thr138=	synonymous_variant	4/9	1	NM_000815.5	P1

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 662 AN: 152272 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00116 AC: 291 AN: 250440 Hom.: 2 AF XY: 0.000987 AC XY: 134 AN XY: 135744

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000550 AC: 803 AN: 1460620 Hom.: 7 Cov.: 35 AF XY: 0.000512 AC XY: 372 AN XY: 726622

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00434 AC: 662 AN: 152390 Hom.: 3 Cov.: 34 AF XY: 0.00439 AC XY: 327 AN XY: 74520

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00521

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GABRD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.013
Dann	Benign	0.67
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0054	T
MutationTaster	Benign	1.0	D
GERP RS		-9.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs77892827; hg19: chr1-1957121;