15-26772766-G-C

Variant names:

• chr15-26772766-G-C
• rs772263479
• NM_000814.6:c.87C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000814.6(GABRB3):​c.87C>G​(p.Asn29Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N29N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GABRB3 NM_000814.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.298
• Publications: 1 publications found

Genes affected

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM1: In a topological_domain Extracellular (size 219) in uniprot entity GBRB3_HUMAN there are 35 pathogenic changes around while only 7 benign (83%) in NM_000814.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24200997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.87C>G	p.Asn29Lys	missense_variant	Exon 2 of 9	ENST00000311550.10	NP_000805.1
GABRB3	NM_021912.5	c.87C>G	p.Asn29Lys	missense_variant	Exon 2 of 9		NP_068712.1
GABRB3	NM_001278631.2	c.-265C>G		5_prime_UTR_variant	Exon 2 of 10		NP_001265560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.87C>G	p.Asn29Lys	missense_variant	Exon 2 of 9	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402940 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 697796

African (AFR) AF: 0.00 AC: 0 AN: 28988

American (AMR) AF: 0.00 AC: 0 AN: 39466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23872

East Asian (EAS) AF: 0.00 AC: 0 AN: 33482

South Asian (SAS) AF: 0.00 AC: 0 AN: 80740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5556

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081400

Other (OTH) AF: 0.00 AC: 0 AN: 57178

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Uncertain:1

Aug 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	L;.;L
PhyloP100		0.30
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.63	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.13	T;D;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.36
MutPred		0.47		.;Gain of ubiquitination at N85 (P = 0.0077);.;
MVP		0.72
MPC		1.4
ClinPred		0.10	T
GERP RS		3.0
PromoterAI		-0.050	Neutral
Varity_R		0.16
gMVP		0.72

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: rs772263479; hg19: chr15-27017913;