12-13615149-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000834.5(GRIN2B):c.1619G>A(p.Arg540His) 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. 11/18 in silico tools predict a damaging 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. R540C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000834.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN2B | NM_000834.5 | c.1619G>A | p.Arg540His | missense_variant | 8/14 | ENST00000609686.4 | |
LOC105369668 | XR_001749013.2 | n.536C>T | non_coding_transcript_exon_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN2B | ENST00000609686.4 | c.1619G>A | p.Arg540His | missense_variant | 8/14 | 1 | NM_000834.5 | P1 | |
ENST00000652867.1 | n.254C>T | non_coding_transcript_exon_variant | 2/3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460874Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726830
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 6 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2014 | - - |
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). - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2020 | The c.1619G>A (p.R540H) alteration is located in exon 7 (coding exon 6) of the GRIN2B gene. This alteration results from a G to A substitution at nucleotide position 1619, causing the arginine (R) at amino acid position 540 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the GRIN2B c.1619G>A alteration was not observed, with coverage at this position. This variant was reported as de novo in multiple individuals with intellectual disability and seizures (Lemke, 2014; Platzer, 2017). This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.R540H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2023 | Published functional studies demonstrate a damaging effect (Swanger et al., 2016; Lemke et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33796003, 28533163, 24272827, 33004838, 28377535, 27839871, 35741674) - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at