1-2019501-C-T

Variant names:

• chr1-2019501-C-T
• rs994082959
• NM_000815.5:c.68+10C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000815.5(GABRD):​c.68+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 437,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GABRD NM_000815.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.101
• 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: ClinGen, Ambry Genetics
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-2019501-C-T is Benign according to our data. Variant chr1-2019501-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 573950.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

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.68+10C>T		intron	N/A	NP_000806.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	ENST00000378585.7	TSL:1 MANE Select	c.68+10C>T		intron	N/A	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.68+10C>T		intron	N/A	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.68+10C>T		intron	N/A	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes AF: 0.000162 AC: 21 AN: 129450 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000841

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000467

Gnomad ASJ AF: 0.00254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000662

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 8 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 36 AN: 307938 Hom.: 0 Cov.: 0 AF XY: 0.0000755 AC XY: 11 AN XY: 145700

African (AFR) AF: 0.00 AC: 0 AN: 6360

American (AMR) AF: 0.000513 AC: 1 AN: 1948

Ashkenazi Jewish (ASJ) AF: 0.00424 AC: 16 AN: 3770

East Asian (EAS) AF: 0.00 AC: 0 AN: 7480

South Asian (SAS) AF: 0.00 AC: 0 AN: 5660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5908

Middle Eastern (MID) AF: 0.00121 AC: 1 AN: 828

European-Non Finnish (NFE) AF: 0.0000265 AC: 7 AN: 263840

Other (OTH) AF: 0.000906 AC: 11 AN: 12144

GnomAD4 genome AF: 0.000162 AC: 21 AN: 129450 Hom.: 0 Cov.: 28 AF XY: 0.000191 AC XY: 12 AN XY: 62710

African (AFR) AF: 0.0000841 AC: 3 AN: 35672

American (AMR) AF: 0.000467 AC: 6 AN: 12858

Ashkenazi Jewish (ASJ) AF: 0.00254 AC: 8 AN: 3150

East Asian (EAS) AF: 0.00 AC: 0 AN: 3498

South Asian (SAS) AF: 0.00 AC: 0 AN: 3482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000662 AC: 4 AN: 60384

Other (OTH) AF: 0.00 AC: 0 AN: 1780

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		0.10
PromoterAI		0.042	Neutral

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: rs994082959; hg19: chr1-1950940;