rs796052515

Variant names:

• chr5-162153300-C-T
• rs796052515
• NM_198904.4:c.1360C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-162153300-C-T
• chr5-162153300-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_198904.4(GABRG2):​c.1360C>T​(p.Arg454Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R454Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.75
• Publications: 4 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 5-162153300-C-T is Pathogenic according to our data. Variant chr5-162153300-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205556.

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.1360C>T	p.Arg454Trp	missense	Exon 10 of 10	NP_944494.1	P18507-2
	GABRG2	NM_198903.2		c.1480C>T	p.Arg494Trp	missense	Exon 11 of 11	NP_944493.2	P18507-3
	GABRG2	NM_001375343.1		c.1456C>T	p.Arg486Trp	missense	Exon 10 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.1360C>T	p.Arg454Trp	missense	Exon 10 of 10	ENSP00000491909.2	P18507-2
	GABRG2	ENST00000414552.6	TSL:1	c.1480C>T	p.Arg494Trp	missense	Exon 11 of 11	ENSP00000410732.2	P18507-3
	GABRG2	ENST00000639111.2	TSL:1	c.1336C>T	p.Arg446Trp	missense	Exon 9 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.85		Loss of methylation at R446 (P = 0.0159)
MVP		0.89
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.66
gMVP		0.97
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs796052515; hg19: chr5-161580306; COSMIC: COSV62716724; COSMIC: COSV62716724;