rs1555103971
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong
The NM_000834.5(GRIN2B):c.2087G>A(p.Arg696His) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R696C) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GRIN2B
NM_000834.5 missense
NM_000834.5 missense
Scores
10
4
2
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
GRIN2B (HGNC:4586): (glutamate ionotropic receptor NMDA type subunit 2B) This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000834.5
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr12-13571889-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2574431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, GRIN2B
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
?
Variant 12-13571888-C-T is Pathogenic according to our data. Variant chr12-13571888-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 489393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13571888-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN2B | NM_000834.5 | c.2087G>A | p.Arg696His | missense_variant | 11/14 | ENST00000609686.4 | |
GRIN2B | NM_001413992.1 | c.2087G>A | p.Arg696His | missense_variant | 12/15 | ||
GRIN2B | XM_005253351.3 | c.-43-1871G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN2B | ENST00000609686.4 | c.2087G>A | p.Arg696His | missense_variant | 11/14 | 1 | NM_000834.5 | P1 | |
GRIN2B | ENST00000637214.1 | c.69+36715G>A | intron_variant | 5 | |||||
GRIN2B | ENST00000628166.2 | n.347G>A | non_coding_transcript_exon_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727212
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461824
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727212
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 6 Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | May 27, 2019 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as "variant, likely mutation" and reported on 11/25/2014 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
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). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2023 | Published functional studies demonstrate enhanced glutamate potency (Swanger et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28377535, 27818011, 31209962, 31144778, 28714951, 31981491, 33004838, 27839871) - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2019 | - - |
Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 696 of the GRIN2B protein (p.Arg696His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability, developmental delay, and autistic features (PMID: 27839871, 28377535). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 489393). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GRIN2B function (PMID: 27839871). For these reasons, this variant has been classified as Pathogenic. - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
Complex neurodevelopmental disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Sep 05, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-09-05 and interpreted as Likely Pathogenic. Variant was initially reported on 2014-11-25 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.043);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at