1-2019488-C-T

Variant names:

• chr1-2019488-C-T
• rs1658715532
• NM_000815.5:c.65C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000815.5(GABRD):​c.65C>T​(p.Thr22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000181 in 1,105,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T22A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2973422).

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.65C>T	p.Thr22Ile	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.65C>T	p.Thr22Ile	missense	Exon 1 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.65C>T	p.Thr22Ile	missense	Exon 1 of 8	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.65C>T	p.Thr22Ile	missense	Exon 1 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes AF: 0.00000689 AC: 1 AN: 145218 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000251

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 AF: 0.00000104 AC: 1 AN: 960260 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 450918

African (AFR) AF: 0.00 AC: 0 AN: 18856

American (AMR) AF: 0.00 AC: 0 AN: 4634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9250

East Asian (EAS) AF: 0.00 AC: 0 AN: 14578

South Asian (SAS) AF: 0.00 AC: 0 AN: 18276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2264

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 844040

Other (OTH) AF: 0.00 AC: 0 AN: 35202

GnomAD4 genome AF: 0.00000689 AC: 1 AN: 145218 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 70802

African (AFR) AF: 0.0000251 AC: 1 AN: 39864

American (AMR) AF: 0.00 AC: 0 AN: 14646

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4504

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65628

Other (OTH) AF: 0.00 AC: 0 AN: 1978

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Idiopathic generalized epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.30	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.50	T
Polyphen		0.037	B
Vest4		0.13
MutPred		0.39		Gain of helix (P = 0.0854)
MVP		0.42
MPC		0.86
ClinPred		0.15	T
GERP RS		2.9
PromoterAI		0.055	Neutral
Varity_R		0.080
gMVP		0.38
Mutation Taster		=94/6	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: rs1658715532; hg19: chr1-1950927;