15-26642413-GTA-GTATA

Variant names:

• chr15-26642413-G-GTA
• rs551896139
• NM_000814.6:c.241-20881_241-20880dupTA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000814.6(GABRB3):​c.241-20881_241-20880dupTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,176,028 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (9 hom.)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.318
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 15-26642413-G-GTA is Benign according to our data. Variant chr15-26642413-G-GTA is described in ClinVar as Likely_benign. ClinVar VariationId is 445708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 513 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.241-20881_241-20880dupTA		intron_variant	Intron 3 of 8	ENST00000311550.10	NP_000805.1
GABRB3	NM_021912.5	c.241-20881_241-20880dupTA		intron_variant	Intron 3 of 8		NP_068712.1
GABRB3	NM_001191320.2	c.-15-20881_-15-20880dupTA		intron_variant	Intron 1 of 6		NP_001178249.1
GABRB3	NM_001278631.2	c.-16+18_-16+19dupTA		intron_variant	Intron 4 of 9		NP_001265560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.241-20880_241-20879insTA		intron_variant	Intron 3 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152060 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00992

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00355 AC: 3639 AN: 1023850 Hom.: 9 Cov.: 14 AF XY: 0.00343 AC XY: 1737 AN XY: 506018

African (AFR) AF: 0.000547 AC: 12 AN: 21954

American (AMR) AF: 0.000923 AC: 25 AN: 27080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14586

East Asian (EAS) AF: 0.00 AC: 0 AN: 12144

South Asian (SAS) AF: 0.0000411 AC: 3 AN: 72910

European-Finnish (FIN) AF: 0.0150 AC: 185 AN: 12302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00401 AC: 3294 AN: 821242

Other (OTH) AF: 0.00318 AC: 120 AN: 37696

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152178 Hom.: 3 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74392

African (AFR) AF: 0.000723 AC: 30 AN: 41520

American (AMR) AF: 0.00118 AC: 18 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00992 AC: 105 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00475 Hom.: 1

Bravo AF: 0.00228

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs551896139; hg19: chr15-26887560;