rs878854144

Variant names:

• chr5-162097839-CG-C
• rs878854144
• NM_198904.4:c.530delG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The NM_198904.4(GABRG2):​c.530delG​(p.Arg177GlnfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.82
• Publications: 1 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-162097839-CG-C is Pathogenic according to our data. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-162097839-CG-C is described in CliVar as Pathogenic. Clinvar id is 238189.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.530delG	p.Arg177GlnfsTer6	frameshift_variant	Exon 4 of 10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.530delG	p.Arg177GlnfsTer6	frameshift_variant	Exon 4 of 10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 Pathogenic:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg177Glnfs*6) in the GABRG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GABRG2 are known to be pathogenic (PMID: 22539854, 22750526, 24407264). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GABRG2-related conditions (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 238189). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878854144; hg19: chr5-161524845;