rs397514737

Variant names:

• chr5-162149153-G-A
• rs397514737
• NM_198904.4:c.968G>A

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.968G>A​(p.Arg323Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: "SCV000241125: Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.88
• Publications: 21 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: G2P, Ambry Genetics, 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: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000241125: Published functional studies demonstrate impaired protein function (Reinthaler et. al., 2015; Absalom et al., 2019); SCV001221884: Experimental studies have shown that this missense change affects GABRG2 function (PMID: 27864268).; SCV005417149: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000851296: Electrophysiology functional studies indicate this variant results in altered GABAA-R chloride channel kinetics (Reinthaler EM et al. Ann. Neurol., 2015 Jun;77:972-86).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr5-162149152-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 205549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 5-162149153-G-A is Pathogenic according to our data. Variant chr5-162149153-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 60708.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.968G>A	p.Arg323Gln	missense	Exon 8 of 10	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.1088G>A	p.Arg363Gln	missense	Exon 9 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.1088G>A	p.Arg363Gln	missense	Exon 9 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.968G>A	p.Arg323Gln	missense	Exon 8 of 10	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.1088G>A	p.Arg363Gln	missense	Exon 9 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.968G>A	p.Arg323Gln	missense	Exon 8 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251162 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 Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Developmental and epileptic encephalopathy, 74 (2)
2	-	-	not provided (2)
1	-	-	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 (1)
1	-	-	Generalized epilepsy with febrile seizures plus 3 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.85		Gain of ubiquitination at K324 (P = 0.0418)
MVP		0.89
MPC		2.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397514737; hg19: chr5-161576159; COSMIC: COSV62717474;