rs148120771

chr1-2029250-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000815.5(GABRD):c.831C>T(p.Pro277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,563,878 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: GABRD NM_000815.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049646497).
• BP6: Variant 1-2029250-C-T is Benign according to our data. Variant chr1-2029250-C-T is described in ClinVar as [Benign]. Clinvar id is 460015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRD	NM_000815.5	c.831C>T	p.Pro277=	synonymous_variant	7/9	ENST00000378585.7
GABRD	XM_017000936.2	c.1536C>T	p.Pro512=	synonymous_variant	6/8
GABRD	XM_011541194.4	c.870C>T	p.Pro290=	synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRD	ENST00000378585.7	c.831C>T	p.Pro277=	synonymous_variant	7/9	1	NM_000815.5	P1

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 152 AN: 152264 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000230 AC: 40 AN: 173744 Hom.: 1 AF XY: 0.000205 AC XY: 19 AN XY: 92512

Gnomad AFR exome AF: 0.00348

Gnomad AMR exome AF: 0.0000764

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000792

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000138

Gnomad OTH exome AF: 0.000206

GnomAD4 exome AF: 0.0000772 AC: 109 AN: 1411496 Hom.: 1 Cov.: 33 AF XY: 0.0000774 AC XY: 54 AN XY: 697930

Gnomad4 AFR exome AF: 0.00265

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000735

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000997 AC: 152 AN: 152382 Hom.: 1 Cov.: 34 AF XY: 0.00105 AC XY: 78 AN XY: 74516

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000615 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.00344 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000274 AC: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	2.0
Dann	Benign	0.78
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0050	T
MutationTaster	Benign	1.0	D
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: rs148120771; hg19: chr1-1960689; COSMIC: COSV66079986; COSMIC: COSV66079986;