NM_000815.5:c.831C>T

Variant names:

• chr1-2029250-C-T
• rs148120771
• NM_000815.5:c.831C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000815.5(GABRD):​c.831C>T​(p.Pro277Pro) 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
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 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 VariationId is 460015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BS2: High AC in GnomAd4 at 152 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	NM_000815.5	MANE Select	c.831C>T	p.Pro277Pro	synonymous	Exon 7 of 9	NP_000806.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	ENST00000378585.7	TSL:1 MANE Select	c.831C>T	p.Pro277Pro	synonymous	Exon 7 of 9	ENSP00000367848.4
	GABRD	ENST00000638411.1	TSL:5	c.862C>T	p.Arg288Cys	missense	Exon 7 of 9	ENSP00000491632.1
	GABRD	ENST00000638771.1	TSL:3	c.831C>T	p.Pro277Pro	synonymous	Exon 7 of 8	ENSP00000492435.1

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

GnomAD2 exomes AF: 0.000230 AC: 40 AN: 173744 AF XY: 0.000205

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 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

African (AFR) AF: 0.00265 AC: 85 AN: 32100

American (AMR) AF: 0.000135 AC: 5 AN: 37172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36780

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000735 AC: 8 AN: 1088242

Other (OTH) AF: 0.000153 AC: 9 AN: 58756

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

African (AFR) AF: 0.00361 AC: 150 AN: 41588

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

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

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
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
PhyloP100		-2.3
GERP RS		-3.4
Mutation Taster		=99/1	polymorphism

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: rs148120771; hg19: chr1-1960689; COSMIC: COSV66079986; COSMIC: COSV66079986;