rs121434580

Variant names:

• chr1-2027636-A-C
• rs121434580
• NM_000815.5:c.530A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000815.5(GABRD):​c.530A>C​(p.Glu177Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 5.73
• Publications: 16 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5	c.530A>C	p.Glu177Ala	missense_variant	Exon 5 of 9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2	c.1235A>C	p.Glu412Ala	missense_variant	Exon 4 of 8		XP_016856425.1
GABRD	XM_011541194.4	c.569A>C	p.Glu190Ala	missense_variant	Exon 5 of 9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.530A>C	p.Glu177Ala	missense_variant	Exon 5 of 9	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Generalized epilepsy with febrile seizures plus type 5 Other:1

Jul 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.;.;.;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;T;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.19	N;.;.;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.011	D;.;.;.;.;.
Sift4G	Benign	0.11	T;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.78
MutPred		0.51		Loss of disorder (P = 0.0714);Loss of disorder (P = 0.0714);Loss of disorder (P = 0.0714);Loss of disorder (P = 0.0714);.;.;
MVP		0.72
MPC		1.3
ClinPred		0.93	D
GERP RS		3.1
PromoterAI		-0.017	Neutral
Varity_R		0.41
gMVP		0.47
Mutation Taster		=64/36	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: rs121434580; hg19: chr1-1959075;