chr12-13567164-C-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000834.5(GRIN2B):c.2459G>C(p.Gly820Ala) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G820E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN2B | NM_000834.5 | c.2459G>C | p.Gly820Ala | missense_variant | 13/14 | ENST00000609686.4 | |
GRIN2B | NM_001413992.1 | c.2459G>C | p.Gly820Ala | missense_variant | 14/15 | ||
GRIN2B | XM_005253351.3 | c.245G>C | p.Gly82Ala | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN2B | ENST00000609686.4 | c.2459G>C | p.Gly820Ala | missense_variant | 13/14 | 1 | NM_000834.5 | P1 | |
GRIN2B | ENST00000637214.1 | c.69+41439G>C | intron_variant | 5 | |||||
GRIN2B | ENST00000628166.2 | n.719G>C | non_coding_transcript_exon_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2021 | Published functional studies demonstrate that G820A stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability (Amin et al., 2018); This variant is associated with the following publications: (PMID: 28867141, 27818011, 28135719, 28856709, 28377535, 29681796, 30217972, 28191890, 33490948, 32144935, 33176815) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Intellectual disability, autosomal dominant 6 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 21, 2023 | PS3_Moderate, PM2, PM6_Strong, PP2, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 04, 2017 | This variant was identified as de novo (maternity and paternity confirmed). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Feb 08, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PS2, PM1, PM2, PM5, PP2, PP3 - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2019 | - - |
Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 13, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly820 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25356899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 GRIN2B protein function. ClinVar contains an entry for this variant (Variation ID: 208643). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy and developmental delay (PMID: 28856709; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs797044849, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 820 of the GRIN2B protein (p.Gly820Ala). - |
Complex neurodevelopmental disorder Pathogenic:1
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Oct 22, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-22 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at