rs1554100923

chr5-162149212-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_198904.4(GABRG2):c.1027T>C(p.Phe343Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 25) in uniprot entity GBRG2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_198904.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRG2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 5-162149212-T-C is Pathogenic according to our data. Variant chr5-162149212-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521620.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG2	NM_198904.4	c.1027T>C	p.Phe343Leu	missense_variant	8/10	ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2	c.1027T>C	p.Phe343Leu	missense_variant	8/10	1	NM_198904.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;T;D;D;T;T;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
Polyphen		1.0	.;.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.56		.;.;.;.;Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);.;.;Loss of helix (P = 0.2022);
MVP		0.87
MPC		2.7
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554100923; hg19: chr5-161576218;