12-13567170-A-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.2453T>C​(p.Met818Thr) 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. M818L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GRIN2B
NM_000834.5 missense

Scores

12
2
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.32
Variant links:
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 19 ACMG points.

PM1
In a transmembrane_region Helical (size 19) in uniprot entity NMDE2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000834.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-13567171-T-G is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the GRIN2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 118 curated benign missense variants. Gene score misZ: 5.4168 (above the threshold of 3.09). Trascript score misZ: 7.3273 (above the threshold of 3.09). GenCC associations: The gene is linked to autism susceptibility 1, developmental and epileptic encephalopathy, 27, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, West syndrome, intellectual disability, autosomal dominant 6.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant 12-13567170-A-G is Pathogenic according to our data. Variant chr12-13567170-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13567170-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-13567170-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRIN2BNM_000834.5 linkc.2453T>C p.Met818Thr missense_variant Exon 13 of 14 ENST00000609686.4 NP_000825.2 Q13224A0A8D9PHB2
GRIN2BNM_001413992.1 linkc.2453T>C p.Met818Thr missense_variant Exon 14 of 15 NP_001400921.1
GRIN2BXM_005253351.3 linkc.239T>C p.Met80Thr missense_variant Exon 3 of 4 XP_005253408.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRIN2BENST00000609686.4 linkc.2453T>C p.Met818Thr missense_variant Exon 13 of 14 1 NM_000834.5 ENSP00000477455.1 Q13224
GRIN2BENST00000637214.1 linkc.69+41433T>C intron_variant Intron 1 of 1 5 ENSP00000489997.1 A0A1B0GU78
GRIN2BENST00000628166.2 linkn.713T>C non_coding_transcript_exon_variant Exon 5 of 5 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Pathogenic:1
May 06, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant disrupts the p.Met818 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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: 245960). This missense change has been observed in individual(s) with clinical features of GRIN2B-related conditions (PMID: 28377535). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 818 of the GRIN2B protein (p.Met818Thr). -

not provided Pathogenic:1
Mar 15, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (Platzer et al., 2017); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28377535) -

Intellectual disability, autosomal dominant 6 Pathogenic:1
Apr 04, 2017
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-0.36
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.91
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.79
Loss of stability (P = 0.0238);
MVP
0.94
MPC
2.6
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.54
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs879254016; hg19: chr12-13720104; API