rs12520992

Variant names:

• chr5-162142424-A-C
• rs12520992
• NM_198904.4:c.922+108A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-162142424-A-C
• chr5-162142424-A-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198904.4(GABRG2):​c.922+108A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,150,928 control chromosomes in the GnomAD database, including 9,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (810 hom., cov: 32)
  • Exomes 𝑓: 0.12 (8671 hom.)
• Consequence: GABRG2 NM_198904.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.550
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-162142424-A-C is Benign according to our data. Variant chr5-162142424-A-C is described in ClinVar as Benign. ClinVar VariationId is 675186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.922+108A>C		intron_variant	Intron 7 of 9	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.922+108A>C		intron_variant	Intron 7 of 9	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13590 AN: 152158 Hom.: 810 Cov.: 32

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0800

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0748

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.0910

GnomAD4 exome AF: 0.124 AC: 123528 AN: 998652 Hom.: 8671 Cov.: 13 AF XY: 0.122 AC XY: 63098 AN XY: 515372

African (AFR) AF: 0.0240 AC: 583 AN: 24304

American (AMR) AF: 0.0551 AC: 2308 AN: 41908

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2609 AN: 22964

East Asian (EAS) AF: 0.00168 AC: 62 AN: 37006

South Asian (SAS) AF: 0.0773 AC: 5836 AN: 75454

European-Finnish (FIN) AF: 0.0961 AC: 4106 AN: 42726

Middle Eastern (MID) AF: 0.0860 AC: 351 AN: 4082

European-Non Finnish (NFE) AF: 0.145 AC: 102360 AN: 705022

Other (OTH) AF: 0.118 AC: 5313 AN: 45186

GnomAD4 genome AF: 0.0893 AC: 13596 AN: 152276 Hom.: 810 Cov.: 32 AF XY: 0.0860 AC XY: 6407 AN XY: 74466

African (AFR) AF: 0.0273 AC: 1133 AN: 41562

American (AMR) AF: 0.0799 AC: 1223 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3468

East Asian (EAS) AF: 0.00308 AC: 16 AN: 5190

South Asian (SAS) AF: 0.0755 AC: 364 AN: 4820

European-Finnish (FIN) AF: 0.0929 AC: 986 AN: 10618

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9228 AN: 68004

Other (OTH) AF: 0.0910 AC: 192 AN: 2110

Alfa AF: 0.0335 Hom.: 45

Bravo AF: 0.0862

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.68
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12520992; hg19: chr5-161569430;