chr5-162095550-C-T

Variant names:

• chr5-162095550-C-T
• rs11135176
• NM_198904.4:c.315C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001375350.1(GABRG2):​c.-44C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 1,598,584 control chromosomes in the GnomAD database, including 10,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (884 hom., cov: 32)
  • Exomes 𝑓: 0.098 (9821 hom.)
• Consequence: GABRG2 NM_001375350.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.284

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-162095550-C-T is Benign according to our data. Variant chr5-162095550-C-T is described in ClinVar as [Benign]. Clinvar id is 129127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.315C>T	p.Asn105Asn	synonymous_variant	Exon 3 of 10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.315C>T	p.Asn105Asn	synonymous_variant	Exon 3 of 10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12774 AN: 151980 Hom.: 872 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.0808

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0699

GnomAD3 exomes AF: 0.130 AC: 32325 AN: 248550 Hom.: 3386 AF XY: 0.125 AC XY: 16788 AN XY: 134336

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.186

Gnomad FIN exome AF: 0.0806

Gnomad NFE exome AF: 0.0776

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0985 AC: 142433 AN: 1446486 Hom.: 9821 Cov.: 28 AF XY: 0.100 AC XY: 72102 AN XY: 720464

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.307

Gnomad4 ASJ exome AF: 0.0405

Gnomad4 EAS exome AF: 0.256

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.0835

Gnomad4 NFE exome AF: 0.0827

Gnomad4 OTH exome AF: 0.0942

GnomAD4 genome AF: 0.0841 AC: 12795 AN: 152098 Hom.: 884 Cov.: 32 AF XY: 0.0888 AC XY: 6598 AN XY: 74330

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.0808

Gnomad4 NFE AF: 0.0817

Gnomad4 OTH AF: 0.0720

Alfa AF: 0.0775 Hom.: 795

Bravo AF: 0.0893

Asia WGS AF: 0.227 AC: 789 AN: 3476

EpiCase AF: 0.0796

EpiControl AF: 0.0680

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 32% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 30. Only high quality variants are reported. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 13, 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. -

Febrile seizures, familial, 8 Benign:1

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, childhood absence 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Benign:1

Feb 04, 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	-0.38
CADD	Benign	0.43
DANN	Benign	0.64

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: rs11135176; hg19: chr5-161522556; COSMIC: COSV62718265; COSMIC: COSV62718265;