chr5-162067846-C-T

Position:

• chr5-162067846-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198904.4(GABRG2):​c.-154C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0626 in 664,620 control chromosomes in the GnomAD database, including 1,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (321 hom., cov: 31)
  • Exomes 𝑓: 0.064 (1205 hom.)
• Consequence: GABRG2 NM_198904.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.393

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-162067846-C-T is Benign according to our data. Variant chr5-162067846-C-T is described in ClinVar as [Benign]. Clinvar id is 352633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-162067846-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.-154C>T		5_prime_UTR_variant	1/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.-154C>T		5_prime_UTR_variant	1/10	1	NM_198904.4	ENSP00000491909	A1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8821 AN: 151946 Hom.: 321 Cov.: 31

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.0414

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0651

GnomAD4 exome AF: 0.0639 AC: 32762 AN: 512556 Hom.: 1205 Cov.: 5 AF XY: 0.0619 AC XY: 17140 AN XY: 276846

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0710

Gnomad4 EAS exome AF: 0.0403

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0710

Gnomad4 OTH exome AF: 0.0663

GnomAD4 genome AF: 0.0580 AC: 8816 AN: 152064 Hom.: 321 Cov.: 31 AF XY: 0.0581 AC XY: 4318 AN XY: 74304

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.0491

Gnomad4 ASJ AF: 0.0726

Gnomad4 EAS AF: 0.0415

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0697

Gnomad4 OTH AF: 0.0653

Alfa AF: 0.0683 Hom.: 409

Bravo AF: 0.0525

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Epilepsy, childhood absence 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.5
DANN	Benign	0.80

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: rs3219203; hg19: chr5-161494852;