chr12-13567173-T-C

Variant names:

• chr12-13567173-T-C
• rs1555103159
• NM_000834.5:c.2450A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000834.5(GRIN2B):​c.2450A>G​(p.Asn817Ser) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 8 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, 0.916
• PP5: Variant 12-13567173-T-C is Pathogenic according to our data. Variant chr12-13567173-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546556.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.2450A>G	p.Asn817Ser	missense_variant	Exon 13 of 14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.2450A>G	p.Asn817Ser	missense_variant	Exon 14 of 15		NP_001400921.1
GRIN2B	XM_005253351.3	c.236A>G	p.Asn79Ser	missense_variant	Exon 3 of 4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.2450A>G	p.Asn817Ser	missense_variant	Exon 13 of 14	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000637214.1	c.69+41430A>G		intron_variant	Intron 1 of 1	5		ENSP00000489997.1
GRIN2B	ENST00000628166.2	n.710A>G		non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jun 01, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant that is likely pathogenic has been identified in the GRIN2B gene. The N817S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N817S variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with GRIN2B-related disorders (Stenson et al., 2014). However, the N817S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Intellectual disability, autosomal dominant 6 Pathogenic:1

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Oct 13, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N817S variant (also known as c.2450A>G), located in coding exon 11 of the GRIN2B gene, results from an A to G substitution at nucleotide position 2450. The asparagine at codon 817 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 27 Uncertain:1

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 4-year-old male with severe delays, prfound hypotonia, history of spasticity, infantile spasms, hand flapping, dysmorphisms, failure to thrive, global brain volume loss -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.71		Gain of disorder (P = 0.0541);
MVP		0.93
MPC		2.2
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.47
gMVP		0.95

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: rs1555103159; hg19: chr12-13720107;