rs121909673

Variant names:

• chr5-162093965-G-A
• rs121909673
• NM_198904.4:c.245G>A
• GABRG2 p.Arg82Gln

Your query was ambiguous. Multiple possible variants found:

• chr5-162093965-G-A
• chr5-162093965-G-T
• chr5-162093965-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_198904.4(GABRG2):​c.245G>A​(p.Arg82Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000241114: Published functional studies demonstrate the variant disrupts GABAA receptor assembly and reduces receptor current density and current amplitude (PMID:24798517, 12097483)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.44
• Publications: 42 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, Labcorp Genetics (formerly Invitae), G2P
• 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: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000241114: Published functional studies demonstrate the variant disrupts GABAA receptor assembly and reduces receptor current density and current amplitude (PMID: 24798517, 12097483);; SCV000767125: Experimental studies have shown that this missense change affects GABRG2 function (PMID: 11326275, 12097483, 15470132, 15866052, 16510738, 18094250, 25731747).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_198904.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-162093964-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1791457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 5-162093965-G-A is Pathogenic according to our data. Variant chr5-162093965-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.245G>A	p.Arg82Gln	missense	Exon 2 of 10	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.245G>A	p.Arg82Gln	missense	Exon 2 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.245G>A	p.Arg82Gln	missense	Exon 2 of 10	NP_001362272.1	A0A1X7SBZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.245G>A	p.Arg82Gln	missense	Exon 2 of 10	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.245G>A	p.Arg82Gln	missense	Exon 2 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.245G>A	p.Arg82Gln	missense	Exon 2 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250890 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460984 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726802

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111428

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000841 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
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	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.96
gMVP		0.93
Mutation Taster		=2/98	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121909673;

hg19: chr5-161520971;