rs1284336148
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000834.5(GRIN2B):c.3884G>A(p.Arg1295Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1295W) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
GRIN2B
NM_000834.5 missense
NM_000834.5 missense
Scores
2
6
8
Clinical Significance
Conservation
PhyloP100: 5.40
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 Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, GRIN2B
BS2
?
High AC in GnomAdExome4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN2B | NM_000834.5 | c.3884G>A | p.Arg1295Gln | missense_variant | 14/14 | ENST00000609686.4 | |
GRIN2B | NM_001413992.1 | c.3884G>A | p.Arg1295Gln | missense_variant | 15/15 | ||
GRIN2B | XM_005253351.3 | c.1670G>A | p.Arg557Gln | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN2B | ENST00000609686.4 | c.3884G>A | p.Arg1295Gln | missense_variant | 14/14 | 1 | NM_000834.5 | P1 | |
GRIN2B | ENST00000637214.1 | c.69+45249G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152050Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251474Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727248
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152050Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74272
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2016 | - - |
Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 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 not expected to disrupt GRIN2B protein function. ClinVar contains an entry for this variant (Variation ID: 521070). This variant has not been reported in the literature in individuals affected with GRIN2B-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1295 of the GRIN2B protein (p.Arg1295Gln). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of methylation at K1297 (P = 0.1139);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at