rs201306411

Variant names:

• chr1-2025660-C-T
• rs201306411
• NM_000815.5:c.392C>T
• GABRD p.Ser131Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-2025660-C-T
• chr1-2025660-C-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000815.5(GABRD):​c.392C>T​(p.Ser131Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 23 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.392C>T	p.Ser131Leu	missense	Exon 4 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.392C>T	p.Ser131Leu	missense	Exon 4 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.392C>T	p.Ser131Leu	missense	Exon 4 of 8	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.392C>T	p.Ser131Leu	missense	Exon 4 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250616 AF XY: 0.00000736

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460666 Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12 AN XY: 726646

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111974

Other (OTH) AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.030	D
PromoterAI		0.12	Neutral
Varity_R		0.76
gMVP		0.47
Mutation Taster		=67/33	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201306411;

hg19: chr1-1957099;