1-2019429-C-G

Variant names:

• chr1-2019429-C-G
• NM_000815.5:c.6C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000815.5(GABRD):​c.6C>G​(p.Asp2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35
• Publications: 0 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)

ENSG00000233542 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16919997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.6C>G	p.Asp2Glu	missense_variant	Exon 1 of 9	ENST00000378585.7	NP_000806.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.6C>G	p.Asp2Glu	missense_variant	Exon 1 of 9	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147248 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 943704 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 446200

African (AFR) AF: 0.00 AC: 0 AN: 18188

American (AMR) AF: 0.00 AC: 0 AN: 4444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8462

East Asian (EAS) AF: 0.00 AC: 0 AN: 10706

South Asian (SAS) AF: 0.00 AC: 0 AN: 21474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2158

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833664

Other (OTH) AF: 0.00 AC: 0 AN: 33800

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147248 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 71706

African (AFR) AF: 0.00 AC: 0 AN: 40704

American (AMR) AF: 0.00 AC: 0 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4904

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66150

Other (OTH) AF: 0.00 AC: 0 AN: 2010

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6C>G (p.D2E) alteration is located in exon 1 (coding exon 1) of the GABRD gene. This alteration results from a C to G substitution at nucleotide position 6, causing the aspartic acid (D) at amino acid position 2 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.7
DANN	Benign	0.64
DEOGEN2	Benign	0.10	T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.34	T;T;T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;.;.;.;.
PhyloP100		-1.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.18	N;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	1.0	T;.;.;.;.
Sift4G	Benign	0.55	T;.;.;.;.
Polyphen		0.013	B;.;.;.;.
Vest4		0.083
MutPred		0.24		Gain of glycosylation at P4 (P = 0.0915);Gain of glycosylation at P4 (P = 0.0915);Gain of glycosylation at P4 (P = 0.0915);Gain of glycosylation at P4 (P = 0.0915);Gain of glycosylation at P4 (P = 0.0915);
MVP		0.44
MPC		0.70
ClinPred		0.025	T
GERP RS		1.8
PromoterAI		0.031	Neutral
Varity_R		0.069
gMVP		0.34
Mutation Taster		=93/7	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

hg19: chr1-1950868;