chr15-26772759-C-T

Variant names:

• chr15-26772759-C-T
• rs71651682
• NM_000814.6:c.94G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000814.6(GABRB3):​c.94G>A​(p.Gly32Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,980 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GABRB3 NM_000814.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 1.50
• Publications: 27 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29078913).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000814.6. 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
	GABRB3	NM_000814.6	MANE Select	c.94G>A	p.Gly32Arg	missense	Exon 2 of 9	NP_000805.1
	GABRB3	NM_021912.5		c.94G>A	p.Gly32Arg	missense	Exon 2 of 9	NP_068712.1
	GABRB3	NM_001278631.2		c.-258G>A		5_prime_UTR	Exon 2 of 10	NP_001265560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.94G>A	p.Gly32Arg	missense	Exon 2 of 9	ENSP00000308725.5
	GABRB3	ENST00000541819.6	TSL:1	c.262G>A	p.Gly88Arg	missense	Exon 3 of 10	ENSP00000442408.2
	GABRB3	ENST00000299267.9	TSL:1	c.94G>A	p.Gly32Arg	missense	Exon 2 of 9	ENSP00000299267.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 214802 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388980 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000352 AC: 1 AN: 28442

American (AMR) AF: 0.00 AC: 0 AN: 39388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23098

East Asian (EAS) AF: 0.00 AC: 0 AN: 32328

South Asian (SAS) AF: 0.00 AC: 0 AN: 81164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071766

Other (OTH) AF: 0.00 AC: 0 AN: 55814

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)
-	-	-	Epilepsy, childhood absence, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.44
Sift	Benign	0.094	T
Sift4G	Benign	0.12	T
Polyphen		0.025	B
Vest4		0.24
MutPred		0.44		Gain of solvent accessibility (P = 0.019)
MVP		0.99
MPC		1.5
ClinPred		0.97	D
GERP RS		3.8
PromoterAI		-0.0028	Neutral
Varity_R		0.23
gMVP		0.80
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs71651682; hg19: chr15-27017906;