rs397514556

Positions:

• chr12-13611847-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000834.5(GRIN2B):​c.1658C>T​(p.Pro553Leu) 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. P553T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.95

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr12-13611848-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, GRIN2B
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 12-13611847-G-A is Pathogenic according to our data. Variant chr12-13611847-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13611847-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.1658C>T	p.Pro553Leu	missense_variant	9/14	ENST00000609686.4
LOC105369668	XR_001749013.2	n.484+1247G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1658C>T	p.Pro553Leu	missense_variant	9/14	1	NM_000834.5	P1
	ENST00000652867.1	n.203-3251G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 6 Pathogenic:2

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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 07, 2022	- -

Developmental and epileptic encephalopathy, 27 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Aug 03, 2020

The GRIN2B c.1658C>T missense variant is classified as LIKELY PATHOGENIC (PM2, PP3, PP5, PS2) The GRIN2B c.1658C>T missense variant is a single nucleotide change in exon 8 of the GRIN2B gene, which is predicted to change the amino acid proline at position 553 in the protein to leucine. This variant has been reported in a patient with severe intellectual disability and hypotonia, with early post-natal onset (PMID:23033978). In that patient, this variant was found to be de novo and was reported as likely pathogenic (PS2). This variant is in dbSNP (rs397514556) but is absent from population databases (PM2). This variant has been reported in ClinVar as Likely pathogenic by another diagnostic laboratory (Variation ID: VCV000039661.2), and has also been reported as damaging in HGMD (CM1211463) and pathogenic in LOVD (GRIN2B_000083) (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.95	P
Vest4		0.99
MutPred		0.69		Loss of disorder (P = 0.0682);
MVP		0.98
MPC		1.4
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.73
gMVP		1.0

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

Other links and lift over

dbSNP: rs397514556; hg19: chr12-13764781;