rs558718893

Variant names:

• chr1-2028285-C-T
• rs558718893
• NM_000815.5:c.684C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_000815.5(GABRD):​c.684C>T​(p.Phe228Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000608 in 1,611,028 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: GABRD NM_000815.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.07
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-2028285-C-T is Benign according to our data. Variant chr1-2028285-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 529548.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 7 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.684C>T	p.Phe228Phe	synonymous	Exon 6 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.684C>T	p.Phe228Phe	synonymous	Exon 6 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638411.1	TSL:5	c.715C>T	p.Gln239*	stop_gained	Exon 6 of 9	ENSP00000491632.1	A0A1W2PPP1
	GABRD	ENST00000638771.1	TSL:3	c.684C>T	p.Phe228Phe	synonymous	Exon 6 of 8	ENSP00000492435.1	A0A1W2PRC4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 247188 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000624 AC: 91 AN: 1458772 Hom.: 0 Cov.: 32 AF XY: 0.0000703 AC XY: 51 AN XY: 725538

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86112

European-Finnish (FIN) AF: 0.000327 AC: 17 AN: 52024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111088

Other (OTH) AF: 0.0000498 AC: 3 AN: 60264

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.00

EpiControl AF: 0.0000594

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	15
DANN	Benign	0.83
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.1
GERP RS		3.5
Mutation Taster		=96/4	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: rs558718893; hg19: chr1-1959724;