NM_033223.5:c.696C>T

Variant names:

• chr15-27480771-C-T
• rs77771286
• NM_033223.5:c.696C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033223.5(GABRG3):​c.696C>T​(p.Ile232Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 1,613,704 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (109 hom.)
• Consequence: GABRG3 NM_033223.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.736
• Publications: 5 publications found

Genes affected

GABRG3 (HGNC:4088): (gamma-aminobutyric acid type A receptor subunit gamma3) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. The protein encoded by this gene is a gamma subunit, which contains the benzodiazepine binding site. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 15-27480771-C-T is Benign according to our data. Variant chr15-27480771-C-T is described in ClinVar as Benign. ClinVar VariationId is 778095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.736 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00884 (12919/1461412) while in subpopulation MID AF = 0.0187 (108/5768). AF 95% confidence interval is 0.0159. There are 109 homozygotes in GnomAdExome4. There are 6369 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033223.5. 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
	GABRG3	NM_033223.5	MANE Select	c.696C>T	p.Ile232Ile	synonymous	Exon 6 of 10	NP_150092.2	Q99928-1
	GABRG3	NM_001270873.2		c.696C>T	p.Ile232Ile	synonymous	Exon 6 of 6	NP_001257802.1	Q99928-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG3	ENST00000615808.5	TSL:1 MANE Select	c.696C>T	p.Ile232Ile	synonymous	Exon 6 of 10	ENSP00000479113.1	Q99928-1
	GABRG3	ENST00000333743.10	TSL:5	c.159C>T	p.Ile53Ile	synonymous	Exon 3 of 7	ENSP00000331912.7	A0A0A0MR73
	GABRG3	ENST00000554696.5	TSL:3	c.522C>T	p.Ile174Ile	synonymous	Exon 4 of 6	ENSP00000451862.1	H0YJP1

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152174 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00907

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.00874 AC: 2171 AN: 248458 AF XY: 0.00872

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.0562

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00349

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00884 AC: 12919 AN: 1461412 Hom.: 109 Cov.: 31 AF XY: 0.00876 AC XY: 6369 AN XY: 726936

African (AFR) AF: 0.00215 AC: 72 AN: 33476

American (AMR) AF: 0.00394 AC: 176 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0549 AC: 1435 AN: 26120

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39680

South Asian (SAS) AF: 0.00254 AC: 219 AN: 86152

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53388

Middle Eastern (MID) AF: 0.0187 AC: 108 AN: 5768

European-Non Finnish (NFE) AF: 0.00907 AC: 10083 AN: 1111764

Other (OTH) AF: 0.0104 AC: 625 AN: 60366

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152292 Hom.: 8 Cov.: 33 AF XY: 0.00694 AC XY: 517 AN XY: 74476

African (AFR) AF: 0.00204 AC: 85 AN: 41570

American (AMR) AF: 0.00784 AC: 120 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00906 AC: 616 AN: 68016

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0103 Hom.: 9

Bravo AF: 0.00782

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.3
DANN	Benign	0.89
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism

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: rs77771286; hg19: chr15-27725917; COSMIC: COSV61535287; COSMIC: COSV61535287;