rs11135176

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 26 publications found

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]

GABRG2 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 74

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 8

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• self-limited epilepsy with centrotemporal spikes

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375350.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	NM_198904.4	MANE Select	c.315C>T	p.Asn105Asn	synonymous	Exon 3 of 10	NP_944494.1
	GABRG2	NM_001375350.1		c.-44C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	NP_001362279.1
	GABRG2	NM_001375348.1		c.-44C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001362277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.315C>T	p.Asn105Asn	synonymous	Exon 3 of 10	ENSP00000491909.2
	GABRG2	ENST00000414552.6	TSL:1	c.315C>T	p.Asn105Asn	synonymous	Exon 3 of 11	ENSP00000410732.2
	GABRG2	ENST00000639111.2	TSL:1	c.315C>T	p.Asn105Asn	synonymous	Exon 3 of 9	ENSP00000492125.2

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

GnomAD2 exomes AF: 0.130 AC: 32325 AN: 248550 AF XY: 0.125

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 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

African (AFR) AF: 0.0151 AC: 500 AN: 33212

American (AMR) AF: 0.307 AC: 13600 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 1053 AN: 25978

East Asian (EAS) AF: 0.256 AC: 10063 AN: 39356

South Asian (SAS) AF: 0.187 AC: 16020 AN: 85714

European-Finnish (FIN) AF: 0.0835 AC: 4443 AN: 53232

Middle Eastern (MID) AF: 0.0386 AC: 222 AN: 5748

European-Non Finnish (NFE) AF: 0.0827 AC: 90902 AN: 1099164

Other (OTH) AF: 0.0942 AC: 5630 AN: 59752

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

African (AFR) AF: 0.0196 AC: 813 AN: 41530

American (AMR) AF: 0.201 AC: 3060 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3470

East Asian (EAS) AF: 0.227 AC: 1172 AN: 5168

South Asian (SAS) AF: 0.204 AC: 983 AN: 4816

European-Finnish (FIN) AF: 0.0808 AC: 854 AN: 10572

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0817 AC: 5556 AN: 67980

Other (OTH) AF: 0.0720 AC: 152 AN: 2110

Alfa AF: 0.0778 Hom.: 1354

Bravo AF: 0.0893

Asia WGS AF: 0.227 AC: 789 AN: 3476

EpiCase AF: 0.0796

EpiControl AF: 0.0680

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 (1)
-	-	1	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 (1)
-	-	1	Febrile seizures, familial, 8 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.43
DANN	Benign	0.64
PhyloP100		-0.28
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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