5-162067984-GA-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_198904.4(GABRG2):c.-4del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 908,344 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0088 (12 hom., cov: 31)
  • Exomes 𝑓: 0.13 (7 hom.)
• Consequence: GABRG2 NM_198904.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.142

Genes affected

GABRG2 (HGNC:4087): (gamma-aminobutyric acid type A receptor subunit gamma2) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 5-162067984-GA-G is Benign according to our data. Variant chr5-162067984-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 352637.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr5-162067984-GA-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG2	NM_198904.4	c.-4del		5_prime_UTR_variant	1/10	ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2	c.-4del		5_prime_UTR_variant	1/10	1	NM_198904.4	A1

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1224 AN: 139092 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.000609

Gnomad EAS AF: 0.000208

Gnomad SAS AF: 0.000919

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000757

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.135 AC: 103691 AN: 769212 Hom.: 7 Cov.: 0 AF XY: 0.136 AC XY: 50698 AN XY: 373124

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.00882 AC: 1227 AN: 139132 Hom.: 12 Cov.: 31 AF XY: 0.00852 AC XY: 574 AN XY: 67384

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.000609

Gnomad4 EAS AF: 0.000209

Gnomad4 SAS AF: 0.00115

Gnomad4 FIN AF: 0.00378

Gnomad4 NFE AF: 0.000757

Gnomad4 OTH AF: 0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Generalized epilepsy with febrile seizures plus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Severe myoclonic epilepsy in infancy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2018

This alteration is classified as likely benign based on a combination of the following: 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs771282908; hg19: chr5-161494990;