rs20318

Variant names:

• chr15-26773650-G-A
• rs20318
• ENST00000299267.9:c.75C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021912.5(GABRB3):​c.75C>T​(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,562,694 control chromosomes in the GnomAD database, including 27,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2542 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24636 hom.)
• Consequence: GABRB3 NM_021912.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.458

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-26773650-G-A is Benign according to our data. Variant chr15-26773650-G-A is described in ClinVar as [Benign]. Clinvar id is 377904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-26773650-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.458 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_021912.5	c.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 9		NP_068712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000299267.9	c.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 9	1		ENSP00000299267.4
GABRB3	ENST00000541819.6	c.249-878C>T		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000638099.1	c.-20+293C>T		intron_variant	Intron 1 of 8	5		ENSP00000490678.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23744 AN: 151920 Hom.: 2533 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.165

GnomAD3 exomes AF: 0.220 AC: 36319 AN: 165162 Hom.: 4947 AF XY: 0.215 AC XY: 19160 AN XY: 89172

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.318

Gnomad SAS exome AF: 0.230

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.177 AC: 250332 AN: 1410666 Hom.: 24636 Cov.: 32 AF XY: 0.179 AC XY: 124876 AN XY: 697086

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.156 AC: 23756 AN: 152028 Hom.: 2542 Cov.: 32 AF XY: 0.164 AC XY: 12174 AN XY: 74302

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.164

Alfa AF: 0.159 Hom.: 708

Bravo AF: 0.160

Asia WGS AF: 0.255 AC: 861 AN: 3376

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 15, 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 56% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 52. Only high quality variants are reported. -

not provided Benign:2

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Jan 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.96

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs20318; hg19: chr15-27018797; COSMIC: COSV54676650; COSMIC: COSV54676650;