rs200019257

Positions:

• chr1-2030175-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000815.5(GABRD):​c.1252C>T​(p.Arg418Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,569,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.13

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09422678).
• BP6: Variant 1-2030175-C-T is Benign according to our data. Variant chr1-2030175-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 565597.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr1-2030175-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRD	NM_000815.5	c.1252C>T	p.Arg418Trp	missense_variant	9/9	ENST00000378585.7
GABRD	XM_017000936.2	c.1957C>T	p.Arg653Trp	missense_variant	8/8
GABRD	XM_011541194.4	c.1291C>T	p.Arg431Trp	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRD	ENST00000378585.7	c.1252C>T	p.Arg418Trp	missense_variant	9/9	1	NM_000815.5	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000133 AC: 29 AN: 218094 Hom.: 0 AF XY: 0.000152 AC XY: 18 AN XY: 118222

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000578

Gnomad SAS exome AF: 0.0000407

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000163 AC: 231 AN: 1417324 Hom.: 0 Cov.: 32 AF XY: 0.000157 AC XY: 110 AN XY: 700396

Gnomad4 AFR exome AF: 0.0000625

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000743 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 13, 2020

ACMG classification criteria: PM2 -

Idiopathic generalized epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.094	T
MutationTaster	Benign	1.0	N
ClinPred		0.045	T
GERP RS		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200019257; hg19: chr1-1961614;