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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000233542 (HGNC:):

ACMG classification

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

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	NM_000815.5	MANE Select	c.6C>G	p.Asp2Glu	missense	Exon 1 of 9	NP_000806.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	ENST00000378585.7	TSL:1 MANE Select	c.6C>G	p.Asp2Glu	missense	Exon 1 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.6C>G	p.Asp2Glu	missense	Exon 1 of 8	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.6C>G	p.Asp2Glu	missense	Exon 1 of 9	ENSP00000491844.1	A0A1W2PQR3

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.17	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)
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;