chr12-13866186-C-T

Position:

• chr12-13866186-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000834.5(GRIN2B):​c.23G>A​(p.Cys8Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRIN2B. . Gene score misZ 5.4168 (greater than the threshold 3.09). Trascript score misZ 7.3273 (greater than threshold 3.09). GenCC has associacion of gene with autism susceptibility 1, developmental and epileptic encephalopathy, 27, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, West syndrome, intellectual disability, autosomal dominant 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13462076).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.23G>A	p.Cys8Tyr	missense_variant	3/14	ENST00000609686.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.23G>A	p.Cys8Tyr	missense_variant	3/14	1	NM_000834.5	P1
GRIN2B	ENST00000630791.2	c.23G>A	p.Cys8Tyr	missense_variant	4/8	5
GRIN2B	ENST00000627535.2	c.23G>A	p.Cys8Tyr	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000820 AC: 2 AN: 243822 Hom.: 0 AF XY: 0.00000755 AC XY: 1 AN XY: 132480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458318 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725482

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 8 of the GRIN2B protein (p.Cys8Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GRIN2B-related conditions. 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 not expected to disrupt GRIN2B protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;.;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N;.;.
MutationTaster	Benign	0.52	N
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.060	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.24
MutPred		0.55		Loss of methylation at K11 (P = 0.0443);Loss of methylation at K11 (P = 0.0443);Loss of methylation at K11 (P = 0.0443);
MVP		0.15
MPC		1.8
ClinPred		0.12	T
GERP RS		3.6
Varity_R		0.20
gMVP		0.56

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: rs1060503160; hg19: chr12-14019120;