chr15-26625455-C-T

Variant names:

• chr15-26625455-C-T
• rs12438141
• NM_000814.6:c.241-3921G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000814.6(GABRB3):​c.241-3921G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 983,684 control chromosomes in the GnomAD database, including 11,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2187 hom., cov: 32)
  • Exomes 𝑓: 0.15 (9618 hom.)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.608
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-26625455-C-T is Benign according to our data. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-26625455-C-T is described in CliVar as Benign. Clinvar id is 3256811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.241-3921G>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.241-3921G>A		intron_variant	Intron 3 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25523 AN: 151944 Hom.: 2186 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0532

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.151 AC: 125224 AN: 831622 Hom.: 9618 Cov.: 25 AF XY: 0.151 AC XY: 57937 AN XY: 384070

African (AFR) AF: 0.232 AC: 3646 AN: 15740

American (AMR) AF: 0.197 AC: 193 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 769 AN: 5136

East Asian (EAS) AF: 0.0485 AC: 176 AN: 3628

South Asian (SAS) AF: 0.149 AC: 2449 AN: 16438

European-Finnish (FIN) AF: 0.162 AC: 45 AN: 278

Middle Eastern (MID) AF: 0.116 AC: 188 AN: 1618

European-Non Finnish (NFE) AF: 0.150 AC: 113785 AN: 760556

Other (OTH) AF: 0.146 AC: 3973 AN: 27246

GnomAD4 genome AF: 0.168 AC: 25537 AN: 152062 Hom.: 2187 Cov.: 32 AF XY: 0.167 AC XY: 12388 AN XY: 74340

African (AFR) AF: 0.219 AC: 9083 AN: 41428

American (AMR) AF: 0.156 AC: 2387 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3468

East Asian (EAS) AF: 0.0538 AC: 278 AN: 5172

South Asian (SAS) AF: 0.146 AC: 705 AN: 4820

European-Finnish (FIN) AF: 0.143 AC: 1512 AN: 10586

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10555 AN: 67994

Other (OTH) AF: 0.180 AC: 379 AN: 2106

Alfa AF: 0.158 Hom.: 1019

Bravo AF: 0.171

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 36. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.5
DANN	Benign	0.82
PhyloP100		0.61
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: rs12438141; hg19: chr15-26870602;