rs148300882

Positions:

• chr1-2030030-C-A
• chr1-2030030-C-G
• chr1-2030030-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000815.5(GABRD):​c.1107C>A​(p.Gly369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,612,632 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. G369G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: GABRD NM_000815.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -3.11

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006442338).
• BP6: Variant 1-2030030-C-A is Benign according to our data. Variant chr1-2030030-C-A is described in ClinVar as [Benign]. Clinvar id is 460005.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-2030030-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.11 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRD	NM_000815.5	c.1107C>A	p.Gly369=	synonymous_variant	9/9	ENST00000378585.7
GABRD	XM_017000936.2	c.1812C>A	p.Gly604=	synonymous_variant	8/8
GABRD	XM_011541194.4	c.1146C>A	p.Gly382=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRD	ENST00000378585.7	c.1107C>A	p.Gly369=	synonymous_variant	9/9	1	NM_000815.5	P1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00128 AC: 318 AN: 248240 Hom.: 1 AF XY: 0.00137 AC XY: 185 AN XY: 134980

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000804

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.00147 AC: 2149 AN: 1460276 Hom.: 3 Cov.: 32 AF XY: 0.00147 AC XY: 1066 AN XY: 726438

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74494

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00168 AC: 203

EpiCase AF: 0.00158

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	1.9
DANN	Benign	0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0064	T;T
MutationTaster	Benign	1.0	D
GERP RS		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs148300882; hg19: chr1-1961469;