NM_198904.4:c.-154C>T

Variant names:

• chr5-162067846-C-T
• rs3219203
• NM_198904.4:c.-154C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198904.4(GABRG2):​c.-154C>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 0.0626 in 664,620 control chromosomes in the GnomAD database, including 1,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (321 hom., cov: 31)
  • Exomes 𝑓: 0.064 (1205 hom.)
• Consequence: GABRG2 NM_198904.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.393
• Publications: 9 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: G2P, Ambry Genetics, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-162067846-C-T is Benign according to our data. Variant chr5-162067846-C-T is described in ClinVar as Benign. ClinVar VariationId is 352633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198904.4. 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.-154C>T		5_prime_UTR	Exon 1 of 10	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.-154C>T		5_prime_UTR	Exon 1 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.-154C>T		5_prime_UTR	Exon 1 of 10	NP_001362272.1	A0A1X7SBZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.-154C>T		5_prime_UTR	Exon 1 of 10	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.-154C>T		5_prime_UTR	Exon 1 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.-154C>T		5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8821 AN: 151946 Hom.: 321 Cov.: 31

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.0414

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0651

GnomAD4 exome AF: 0.0639 AC: 32762 AN: 512556 Hom.: 1205 Cov.: 5 AF XY: 0.0619 AC XY: 17140 AN XY: 276846

African (AFR) AF: 0.0338 AC: 464 AN: 13724

American (AMR) AF: 0.0430 AC: 1114 AN: 25896

Ashkenazi Jewish (ASJ) AF: 0.0710 AC: 1211 AN: 17046

East Asian (EAS) AF: 0.0403 AC: 1291 AN: 32014

South Asian (SAS) AF: 0.0259 AC: 1404 AN: 54260

European-Finnish (FIN) AF: 0.108 AC: 3455 AN: 31922

Middle Eastern (MID) AF: 0.0701 AC: 259 AN: 3694

European-Non Finnish (NFE) AF: 0.0710 AC: 21649 AN: 305118

Other (OTH) AF: 0.0663 AC: 1915 AN: 28882

GnomAD4 genome AF: 0.0580 AC: 8816 AN: 152064 Hom.: 321 Cov.: 31 AF XY: 0.0581 AC XY: 4318 AN XY: 74304

African (AFR) AF: 0.0313 AC: 1298 AN: 41498

American (AMR) AF: 0.0491 AC: 749 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3472

East Asian (EAS) AF: 0.0415 AC: 214 AN: 5152

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4816

European-Finnish (FIN) AF: 0.117 AC: 1237 AN: 10554

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0697 AC: 4736 AN: 67986

Other (OTH) AF: 0.0653 AC: 138 AN: 2112

Alfa AF: 0.0663 Hom.: 554

Bravo AF: 0.0525

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.5
DANN	Benign	0.80
PhyloP100		-0.39
PromoterAI		-0.015	Neutral
Mutation Taster		=300/0	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: rs3219203; hg19: chr5-161494852;