chr5-162153132-C-T

Variant names:

• chr5-162153132-C-T
• rs121909674
• NM_198904.4:c.1192C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_198903.2(GABRG2):​c.1312C>T​(p.Gln438*) variant causes a stop gained change. 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198903.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.07
• Publications: 59 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-162153132-C-T is Pathogenic according to our data. Variant chr5-162153132-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16209.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198903.2. 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.1192C>T	p.Gln398*	stop_gained	Exon 10 of 10	NP_944494.1
	GABRG2	NM_198903.2		c.1312C>T	p.Gln438*	stop_gained	Exon 11 of 11	NP_944493.2
	GABRG2	NM_001375343.1		c.1288C>T	p.Gln430*	stop_gained	Exon 10 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.1192C>T	p.Gln398*	stop_gained	Exon 10 of 10	ENSP00000491909.2
	GABRG2	ENST00000414552.6	TSL:1	c.1312C>T	p.Gln438*	stop_gained	Exon 11 of 11	ENSP00000410732.2
	GABRG2	ENST00000639111.2	TSL:1	c.1168C>T	p.Gln390*	stop_gained	Exon 9 of 9	ENSP00000492125.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Febrile seizures, familial, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.1
Vest4		0.72
GERP RS		6.0
Mutation Taster		=0/200	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: rs121909674; hg19: chr5-161580138; COSMIC: COSV62718182; COSMIC: COSV62718182;