5-162067984-G-GA

Position:

• chr5-162067984-G-GA

Variant summary

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

The NM_198904.4(GABRG2):​c.-4dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,139,362 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.052 (0 hom.)
• Consequence: GABRG2 NM_198904.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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-G-GA is Benign according to our data. Variant chr5-162067984-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 352636.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 267 AN: 139270 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00130

Gnomad ASJ AF: 0.00364

Gnomad EAS AF: 0.000624

Gnomad SAS AF: 0.00390

Gnomad FIN AF: 0.00109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000740

Gnomad OTH AF: 0.00157

GnomAD4 exome AF: 0.0519 AC: 51900 AN: 1000048 Hom.: 0 Cov.: 0 AF XY: 0.0494 AC XY: 24800 AN XY: 502104

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.0291

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.0580

Gnomad4 OTH exome AF: 0.0472

GnomAD4 genome AF: 0.00193 AC: 269 AN: 139314 Hom.: 1 Cov.: 31 AF XY: 0.00191 AC XY: 129 AN XY: 67450

Gnomad4 AFR AF: 0.00417

Gnomad4 AMR AF: 0.00129

Gnomad4 ASJ AF: 0.00364

Gnomad4 EAS AF: 0.000626

Gnomad4 SAS AF: 0.00392

Gnomad4 FIN AF: 0.00109

Gnomad4 NFE AF: 0.000740

Gnomad4 OTH AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2017

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. -

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;