rs28408173

Positions:

• chr1-2029235-C-T

Variant summary

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

The NM_000815.5(GABRD):​c.816C>T​(p.Ser272Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,569,906 control chromosomes in the GnomAD database, including 20,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1800 hom., cov: 34)
  • Exomes 𝑓: 0.15 (18892 hom.)
• Consequence: GABRD NM_000815.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.476

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.3176806E-5).
• BP6: Variant 1-2029235-C-T is Benign according to our data. Variant chr1-2029235-C-T is described in ClinVar as [Benign]. Clinvar id is 256825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2029235-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.476 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5	c.816C>T	p.Ser272Ser	synonymous_variant	7/9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.1521C>T	p.Ser507Ser	synonymous_variant	6/8		XP_016856425.1
GABRD	XM_011541194.4	c.855C>T	p.Ser285Ser	synonymous_variant	7/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.816C>T	p.Ser272Ser	synonymous_variant	7/9	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19216 AN: 152184 Hom.: 1790 Cov.: 34

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.192 AC: 35320 AN: 184166 Hom.: 4375 AF XY: 0.195 AC XY: 19180 AN XY: 98252

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.472

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.152 AC: 215491 AN: 1417604 Hom.: 18892 Cov.: 33 AF XY: 0.154 AC XY: 108357 AN XY: 701504

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.126 AC: 19243 AN: 152302 Hom.: 1800 Cov.: 34 AF XY: 0.132 AC XY: 9853 AN XY: 74478

Gnomad4 AFR AF: 0.0315

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.155

Alfa AF: 0.124 Hom.: 640

Bravo AF: 0.124

TwinsUK AF: 0.124 AC: 461

ALSPAC AF: 0.138 AC: 531

ESP6500AA AF: 0.0322 AC: 141

ESP6500EA AF: 0.131 AC: 1123

ExAC AF: 0.157 AC: 18364

Asia WGS AF: 0.328 AC: 1140 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	GeneDx	Jun 27, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.45
CADD	Benign	2.2
DANN	Benign	0.72
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.000043	T
GERP RS		-3.4

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: rs28408173; hg19: chr1-1960674; COSMIC: COSV66080067; COSMIC: COSV66080067;