ENST00000639111.2:c.-282C>T

Variant names:

• chr5-162067718-C-T
• rs772816792
• ENST00000639111.2:c.-282C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000639111.2(GABRG2):​c.-282C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 609,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GABRG2 ENST00000639111.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.362
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/151998) while in subpopulation AMR AF = 0.000459 (7/15248). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000639111.2. 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_198903.2		c.-282C>T		5_prime_UTR	Exon 1 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.-282C>T		5_prime_UTR	Exon 1 of 10	NP_001362272.1	A0A1X7SBZ8
	GABRG2	NM_001375344.1		c.-282C>T		5_prime_UTR	Exon 1 of 11	NP_001362273.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000639111.2	TSL:1	c.-282C>T		5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1
	GABRG2	ENST00000943443.1		c.-282C>T		5_prime_UTR	Exon 1 of 10	ENSP00000613502.1
	GABRG2	ENST00000638772.1	TSL:5	c.-282C>T		5_prime_UTR	Exon 1 of 8	ENSP00000491557.1	A0A1W2PPS4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151998 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000166 AC: 76 AN: 457248 Hom.: 0 Cov.: 0 AF XY: 0.000148 AC XY: 36 AN XY: 242540

African (AFR) AF: 0.0000796 AC: 1 AN: 12564

American (AMR) AF: 0.000319 AC: 6 AN: 18832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13800

East Asian (EAS) AF: 0.00 AC: 0 AN: 31512

South Asian (SAS) AF: 0.0000222 AC: 1 AN: 45092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2000

European-Non Finnish (NFE) AF: 0.000224 AC: 62 AN: 277286

Other (OTH) AF: 0.000227 AC: 6 AN: 26480

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151998 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.000459 AC: 7 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67998

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000132

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.75
PhyloP100		0.36
PromoterAI		0.0010	Neutral

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: rs772816792; hg19: chr5-161494724;