rs199803550

Positions:

• chr12-13563292-C-A
• chr12-13563292-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.3946G>T​(p.Ala1316Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,888 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. A1316T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GRIN2B NM_000834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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=0.14239073).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.3946G>T	p.Ala1316Ser	missense_variant	14/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.3946G>T	p.Ala1316Ser	missense_variant	15/15
GRIN2B	XM_005253351.3	c.1732G>T	p.Ala578Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.3946G>T	p.Ala1316Ser	missense_variant	14/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+45311G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Invitae

Jun 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1316 of the GRIN2B protein (p.Ala1316Ser). 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. 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. This variant has not been reported in the literature in individuals affected with GRIN2B-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.57	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.48		Gain of relative solvent accessibility (P = 0.005);
MVP		0.38
MPC		0.54
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.12
gMVP		0.25

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: rs199803550; hg19: chr12-13716226;