NM_198904.4:c.354G>A

Variant names:

• chr5-162097664-G-A
• rs61735412
• NM_198904.4:c.354G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198904.4(GABRG2):​c.354G>A​(p.Ala118Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,612,768 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A118A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (61 hom.)
• Consequence: GABRG2 NM_198904.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.03
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-162097664-G-A is Benign according to our data. Variant chr5-162097664-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198904.4. 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.354G>A	p.Ala118Ala	synonymous	Exon 4 of 10	NP_944494.1
	GABRG2	NM_198903.2		c.354G>A	p.Ala118Ala	synonymous	Exon 4 of 11	NP_944493.2
	GABRG2	NM_001375343.1		c.354G>A	p.Ala118Ala	synonymous	Exon 4 of 10	NP_001362272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.354G>A	p.Ala118Ala	synonymous	Exon 4 of 10	ENSP00000491909.2
	GABRG2	ENST00000414552.6	TSL:1	c.354G>A	p.Ala118Ala	synonymous	Exon 4 of 11	ENSP00000410732.2
	GABRG2	ENST00000639111.2	TSL:1	c.354G>A	p.Ala118Ala	synonymous	Exon 4 of 9	ENSP00000492125.2

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2377 AN: 151884 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00749

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.00423 AC: 1055 AN: 249500 AF XY: 0.00330

Gnomad AFR exome AF: 0.0557

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00190 AC: 2773 AN: 1460766 Hom.: 61 Cov.: 32 AF XY: 0.00165 AC XY: 1199 AN XY: 726740

African (AFR) AF: 0.0573 AC: 1913 AN: 33396

American (AMR) AF: 0.00289 AC: 129 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39666

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5756

European-Non Finnish (NFE) AF: 0.000394 AC: 438 AN: 1111234

Other (OTH) AF: 0.00404 AC: 244 AN: 60334

GnomAD4 genome AF: 0.0157 AC: 2382 AN: 152002 Hom.: 70 Cov.: 32 AF XY: 0.0156 AC XY: 1162 AN XY: 74262

African (AFR) AF: 0.0530 AC: 2197 AN: 41476

American (AMR) AF: 0.00748 AC: 114 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67982

Other (OTH) AF: 0.0166 AC: 35 AN: 2108

Alfa AF: 0.00530 Hom.: 4

Bravo AF: 0.0184

EpiCase AF: 0.000982

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.2
DANN	Benign	0.64
PhyloP100		-1.0
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61735412; hg19: chr5-161524670;