rs796052515
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
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. 12/21 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
Consequence
NM_198904.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRG2 | NM_198904.4 | c.1360C>T | p.Arg454Trp | missense_variant | 10/10 | ENST00000639213.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRG2 | ENST00000639213.2 | c.1360C>T | p.Arg454Trp | missense_variant | 10/10 | 1 | NM_198904.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2013 | p.Arg446Trp (CGG>TGG): c.1336 C>T in exon 9 of the GABRG2 gene (NM_000816.3) The Arg446Trp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Arg446Trp in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a positively charged, polar Arginine residue is replaced by an uncharged non-polar Tryptophan residue and multiple in-silico algorithms predict it may be damaging to the structure/function of the protein. However, while Arg446Trp alters a highly conserved position in the fourth transmembrane domain in the GABRG2 protein, other missense mutations have not been reported in this region of the protein. Therefore, based on the currently available information, Arg446Trp is interpreted as pathogenic. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s). - |
Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GABRG2 protein function. ClinVar contains an entry for this variant (Variation ID: 205556). This missense change has been observed in individual(s) with clinical features of GABRG2-related conditions (PMID: 29655203; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 446 of the GABRG2 protein (p.Arg446Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at