rs2229110

Positions:

• chr1-2025598-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000378585.7(GABRD):​c.330T>C​(p.Gly110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,612,716 control chromosomes in the GnomAD database, including 327,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33159 hom., cov: 34)
  • Exomes 𝑓: 0.63 (294726 hom.)
• Consequence: GABRD ENST00000378585.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.22

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=9.98378E-7).
• BP6: Variant 1-2025598-T-C is Benign according to our data. Variant chr1-2025598-T-C is described in ClinVar as [Benign]. Clinvar id is 256823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2025598-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5	c.330T>C	p.Gly110=	synonymous_variant	4/9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.1035T>C	p.Gly345=	synonymous_variant	3/8		XP_016856425.1
GABRD	XM_011541194.4	c.369T>C	p.Gly123=	synonymous_variant	4/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.330T>C	p.Gly110=	synonymous_variant	4/9	1	NM_000815.5	ENSP00000367848	P1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99494 AN: 151996 Hom.: 33171 Cov.: 34

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.662

GnomAD3 exomes AF: 0.588 AC: 147340 AN: 250576 Hom.: 45286 AF XY: 0.589 AC XY: 79915 AN XY: 135744

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.474

Gnomad FIN exome AF: 0.638

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.630 AC: 920909 AN: 1460604 Hom.: 294726 Cov.: 57 AF XY: 0.627 AC XY: 455681 AN XY: 726602

Gnomad4 AFR exome AF: 0.731

Gnomad4 AMR exome AF: 0.487

Gnomad4 ASJ exome AF: 0.696

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.653

Gnomad4 OTH exome AF: 0.629

GnomAD4 genome AF: 0.654 AC: 99507 AN: 152112 Hom.: 33159 Cov.: 34 AF XY: 0.647 AC XY: 48096 AN XY: 74338

Gnomad4 AFR AF: 0.728

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.641

Gnomad4 NFE AF: 0.656

Gnomad4 OTH AF: 0.658

Alfa AF: 0.666 Hom.: 15282

Bravo AF: 0.654

TwinsUK AF: 0.668 AC: 2477

ALSPAC AF: 0.653 AC: 2516

ESP6500AA AF: 0.731 AC: 3220

ESP6500EA AF: 0.660 AC: 5680

ExAC AF: 0.592 AC: 71860

Asia WGS AF: 0.414 AC: 1444 AN: 3478

EpiCase AF: 0.668

EpiControl AF: 0.667

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.73
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000010	T
MutationTaster	Benign	1.3e-19	P
GERP RS		2.5

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: rs2229110; hg19: chr1-1957037; COSMIC: COSV66080001; COSMIC: COSV66080001;