rs869312868

chr12-13571910-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_000834.5(GRIN2B):c.2065G>A(p.Gly689Ser) 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000834.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRIN2B
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 12-13571910-C-T is Pathogenic according to our data. Variant chr12-13571910-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13571910-C-T is described in Lovd as [Pathogenic]. Variant chr12-13571910-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-13571910-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.2065G>A	p.Gly689Ser	missense_variant	11/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.2065G>A	p.Gly689Ser	missense_variant	12/15
GRIN2B	XM_005253351.3	c.-43-1893G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.2065G>A	p.Gly689Ser	missense_variant	11/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+36693G>A		intron_variant		5
GRIN2B	ENST00000628166.2	n.325G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28867141, 34212862, 34490615, 34673242, 26350515, 27818011, 28377535, 30842224, 31785789, 33860439, 34302356, 35240744, 35238837, 27839871) -

Intellectual disability, autosomal dominant 6 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Sep 09, 2015	This study shows that diverse genetic causes underlie CVI. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 09, 2021	This variant was identified as de novo (maternity and paternity confirmed). -

Developmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Aug 29, 2019

- -

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 689 of the GRIN2B protein (p.Gly689Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GRIN2B-related conditions (PMID: 28377535, 30842224, 34212862). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224818). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GRIN2B protein function. Experimental studies have shown that this missense change affects GRIN2B function (PMID: 34212862). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2023

The p.Gly689Ser variant in GRIN2B has been reported as a de novo variant in 8 individuals in the literature (Bosch 2016 PMID: 26350515, Platzer 2017 PMID: 28377535, Iwama 2019 PMID: 30842224, Kwok 2020 PMID: 33229608, Kellner 2021 PMID: 34212862) in association with complex neurodevelopmental disorder (intellectual disability, autosomal dominant 6, with or without epilepsy). The variant was absent from large population studies (gnomAD). This variant has also been reported in ClinVar as de novo by multiple submitters (Variation ID: 224818). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function by decreasing glutamate potency and producing a dominant negative effect on wildtype subunits (Kellner 2021 PMID: 34212862). This variant lies in the S2 ligand-binding domain, and pathogenic missense variants associated with disease cluster in the S1 and S2 ligand-binding domains (Platzer 2017 PMID: 28377535). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder. ACMG/AMP Criteria applied: PS4, PM6_VS, PM1, PS3_Supporting, PP3, PM2_Supporting. -

Complex neurodevelopmental disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Feb 17, 2016

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-17 and interpreted as Likely Pathogenic. Variant was initially reported on 2015-12-21 by GTR ID of laboratory name 283396. The reporting laboratory might also submit to ClinVar. -

Developmental and epileptic encephalopathy, 27 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Sep 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.54		Gain of disorder (P = 0.0764);
MVP		0.96
MPC		2.4
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.61
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs869312868; hg19: chr12-13724844; COSMIC: COSV101662955;