rs41307846

Variant names:

• chr1-2028260-G-A
• rs41307846
• NM_000815.5:c.659G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000815.5(GABRD):​c.659G>A​(p.Arg220His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,611,710 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (27 hom., cov: 32)
  • Exomes 𝑓: 0.022 (410 hom.)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.91
• Publications: 27 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004277706).
• BP6: Variant 1-2028260-G-A is Benign according to our data. Variant chr1-2028260-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 16213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2540/151982) while in subpopulation NFE AF = 0.0232 (1578/67976). AF 95% confidence interval is 0.0223. There are 27 homozygotes in GnomAd4. There are 1267 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2540 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000815.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	NM_000815.5	MANE Select	c.659G>A	p.Arg220His	missense	Exon 6 of 9	NP_000806.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	ENST00000378585.7	TSL:1 MANE Select	c.659G>A	p.Arg220His	missense	Exon 6 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.659G>A	p.Arg220His	missense	Exon 6 of 8	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.743G>A	p.Arg248His	missense	Exon 6 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2542 AN: 151866 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00380

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0173 AC: 4286 AN: 248398 AF XY: 0.0177

Gnomad AFR exome AF: 0.00383

Gnomad AMR exome AF: 0.00964

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0217 AC: 31735 AN: 1459728 Hom.: 410 Cov.: 32 AF XY: 0.0214 AC XY: 15522 AN XY: 726134

African (AFR) AF: 0.00308 AC: 103 AN: 33456

American (AMR) AF: 0.0101 AC: 453 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 409 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00634 AC: 546 AN: 86162

European-Finnish (FIN) AF: 0.0402 AC: 2093 AN: 52108

Middle Eastern (MID) AF: 0.0180 AC: 102 AN: 5664

European-Non Finnish (NFE) AF: 0.0240 AC: 26727 AN: 1111602

Other (OTH) AF: 0.0216 AC: 1301 AN: 60304

GnomAD4 genome AF: 0.0167 AC: 2540 AN: 151982 Hom.: 27 Cov.: 32 AF XY: 0.0171 AC XY: 1267 AN XY: 74296

African (AFR) AF: 0.00379 AC: 157 AN: 41388

American (AMR) AF: 0.0162 AC: 247 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.0364 AC: 384 AN: 10562

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1578 AN: 67976

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0206 Hom.: 20

Bravo AF: 0.0153

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00455 AC: 20

ESP6500EA AF: 0.0229 AC: 197

ExAC AF: 0.0165 AC: 2002

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0223

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	GABRD-related disorder (1)
-	-	1	Generalized epilepsy with febrile seizures plus type 5 (1)
-	-	1	Idiopathic generalized epilepsy (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.58
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N
PhyloP100		1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.18
Sift	Benign	0.73	T
Sift4G	Benign	0.65	T
Polyphen		0.021	B
Vest4		0.12
MPC		0.95
ClinPred		0.0055	T
GERP RS		1.5
Varity_R		0.050
gMVP		0.49
Mutation Taster		=97/3	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: rs41307846; hg19: chr1-1959699; COSMIC: COSV107493643; COSMIC: COSV107493643;