rs148908731

Positions:

• chr1-2029194-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000815.5(GABRD):​c.775G>A​(p.Val259Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,566,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.991

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008660853).
• BP6: Variant 1-2029194-G-A is Benign according to our data. Variant chr1-2029194-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235308.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr1-2029194-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5	c.775G>A	p.Val259Ile	missense_variant	7/9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.1480G>A	p.Val494Ile	missense_variant	6/8		XP_016856425.1
GABRD	XM_011541194.4	c.814G>A	p.Val272Ile	missense_variant	7/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.775G>A	p.Val259Ile	missense_variant	7/9	1	NM_000815.5	ENSP00000367848	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152246 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000890 AC: 16 AN: 179708 Hom.: 0 AF XY: 0.0000942 AC XY: 9 AN XY: 95546

Gnomad AFR exome AF: 0.000664

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000230

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000526

Gnomad OTH exome AF: 0.000404

GnomAD4 exome AF: 0.0000707 AC: 100 AN: 1413674 Hom.: 0 Cov.: 31 AF XY: 0.0000587 AC XY: 41 AN XY: 699056

Gnomad4 AFR exome AF: 0.000654

Gnomad4 AMR exome AF: 0.000108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000108

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000533

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152364 Hom.: 1 Cov.: 34 AF XY: 0.000336 AC XY: 25 AN XY: 74508

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000108 Hom.: 1

Bravo AF: 0.000487

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000144 AC: 17

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Feb 01, 2016

- -

EEG abnormality Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Sep 02, 2016

- -

GABRD-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic generalized epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.32
DANN	Benign	0.69
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.0087	T
MutationTaster	Benign	0.89	N
ClinPred		0.0022	T
GERP RS		-3.2

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: rs148908731; hg19: chr1-1960633;