1-2019489-C-G

Variant names:

• chr1-2019489-C-G
• rs1658715570
• NM_000815.5:c.66C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000815.5(GABRD):​c.66C>G​(p.Thr22Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: GABRD NM_000815.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.002653
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.694
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-2019489-C-G is Benign according to our data. Variant chr1-2019489-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2974456.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.694 with no splicing effect.

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.66C>G	p.Thr22Thr	splice_region synonymous	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.66C>G	p.Thr22Thr	splice_region synonymous	Exon 1 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.66C>G	p.Thr22Thr	splice_region synonymous	Exon 1 of 8	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.66C>G	p.Thr22Thr	splice_region synonymous	Exon 1 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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	-0.43
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		0.69
PromoterAI		0.10	Neutral
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.066
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: rs1658715570; hg19: chr1-1950928;