rs869312868

Variant names:

• chr12-13571910-C-T
• rs869312868
• NM_000834.5:c.2065G>A

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:11
• 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 topological_domain Extracellular (size 170) in uniprot entity NMDE2_HUMAN there are 37 pathogenic changes around while only 0 benign (100%) in NM_000834.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.806
• 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 rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.2065G>A	p.Gly689Ser	missense_variant	Exon 11 of 14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.2065G>A	p.Gly689Ser	missense_variant	Exon 12 of 15		NP_001400921.1
GRIN2B	XM_005253351.3	c.-43-1893G>A		intron_variant	Intron 1 of 3		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.2065G>A	p.Gly689Ser	missense_variant	Exon 11 of 14	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000637214.1	c.69+36693G>A		intron_variant	Intron 1 of 1	5		ENSP00000489997.1
GRIN2B	ENST00000628166.2	n.325G>A		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 6 Pathogenic:3

Oct 15, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest a damaging effect of the variant on the gene or gene product [3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000224818).The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 28377535).A different missense change at the same codon (p.Gly689Cys) has been reported to be associated with GRIN2B related disorder (PMID: 34212862). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 09, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This study shows that diverse genetic causes underlie CVI. -

Jul 09, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Pathogenic:2

Mar 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 27 Pathogenic:2

Sep 03, 2018

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2023

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3: In vitro functional studies showed this variant impacts protein function (PMID: 34212862). PS4 (applied as moderate) reported in various publications. PM1: Located in a mutational hot spot and/or critical and well-established functional domain (PMID: 28377535). PM2: Absent in the population databases. PM6: De novo without the confirmation of paternity and maternity PP2: GRIN2b has a low rate of benign missense variation (Z score: 7.34) PP3: In silico scores predict the variant to be damaging to the protein function. PP5: Reported as pathogenic variant in ClinVar. -

Developmental disorder Pathogenic:1

Aug 29, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 16, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 17, 2016

GenomeConnect - Simons Searchlight

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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. -

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
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;