rs2300272

Variant names:

• chr12-13803645-G-A
• rs2300272
• NM_000834.5:c.412-49730C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000834.5(GRIN2B):​c.412-49730C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 152,080 control chromosomes in the GnomAD database, including 16,277 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (16277 hom., cov: 34)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• Publications: 11 publications found

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]

GRIN2B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• developmental and epileptic encephalopathy, 27

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• intellectual disability, autosomal dominant 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.412-49730C>T		intron_variant	Intron 3 of 13	ENST00000609686.4	NP_000825.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.412-49730C>T		intron_variant	Intron 3 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.412-49730C>T		intron_variant	Intron 4 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000714048.1	n.412-49730C>T		intron_variant	Intron 3 of 12			ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67797 AN: 151962 Hom.: 16273 Cov.: 34

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.494

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.446 AC: 67828 AN: 152080 Hom.: 16277 Cov.: 34 AF XY: 0.441 AC XY: 32820 AN XY: 74348

African (AFR) AF: 0.279 AC: 11555 AN: 41480

American (AMR) AF: 0.454 AC: 6937 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2108 AN: 3470

East Asian (EAS) AF: 0.262 AC: 1357 AN: 5172

South Asian (SAS) AF: 0.478 AC: 2301 AN: 4818

European-Finnish (FIN) AF: 0.456 AC: 4825 AN: 10574

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37107 AN: 67984

Other (OTH) AF: 0.491 AC: 1037 AN: 2110

Alfa AF: 0.523 Hom.: 35327

Bravo AF: 0.438

Asia WGS AF: 0.410 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.43
DANN	Benign	0.47
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2300272; hg19: chr12-13956579;