15-26624917-C-T

Variant names:

• chr15-26624917-C-T
• rs12595837
• NM_000814.6:c.241-3383G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000814.6(GABRB3):​c.241-3383G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 985,186 control chromosomes in the GnomAD database, including 48,579 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (7209 hom., cov: 33)
  • Exomes 𝑓: 0.31 (41370 hom.)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.624
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.241-3383G>A		intron_variant	Intron 3 of 8	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.241-3383G>A		intron_variant	Intron 3 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40941 AN: 151990 Hom.: 7199 Cov.: 33

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.310 AC: 258176 AN: 833078 Hom.: 41370 Cov.: 32 AF XY: 0.309 AC XY: 119050 AN XY: 384714

African (AFR) AF: 0.0539 AC: 851 AN: 15790

American (AMR) AF: 0.328 AC: 323 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1618 AN: 5154

East Asian (EAS) AF: 0.788 AC: 2860 AN: 3630

South Asian (SAS) AF: 0.403 AC: 6640 AN: 16458

European-Finnish (FIN) AF: 0.414 AC: 116 AN: 280

Middle Eastern (MID) AF: 0.233 AC: 378 AN: 1620

European-Non Finnish (NFE) AF: 0.310 AC: 236402 AN: 761862

Other (OTH) AF: 0.329 AC: 8988 AN: 27300

GnomAD4 genome AF: 0.269 AC: 40970 AN: 152108 Hom.: 7209 Cov.: 33 AF XY: 0.279 AC XY: 20709 AN XY: 74344

African (AFR) AF: 0.0836 AC: 3472 AN: 41524

American (AMR) AF: 0.304 AC: 4652 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1105 AN: 3472

East Asian (EAS) AF: 0.785 AC: 4043 AN: 5148

South Asian (SAS) AF: 0.405 AC: 1950 AN: 4810

European-Finnish (FIN) AF: 0.366 AC: 3876 AN: 10576

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20947 AN: 67970

Other (OTH) AF: 0.246 AC: 519 AN: 2114

Alfa AF: 0.288 Hom.: 4148

Bravo AF: 0.255

Asia WGS AF: 0.507 AC: 1763 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.4
DANN	Benign	0.83
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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: rs12595837; hg19: chr15-26870064;