rs2284411

Variant names:

• chr12-13713238-C-T
• rs2284411
• NM_000834.5:c.1011-37379G>A

Variant summary

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

The NM_000834.5(GRIN2B):​c.1011-37379G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 151,696 control chromosomes in the GnomAD database, including 8,909 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 0.34 (8909 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 22 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1011-37379G>A		intron_variant	Intron 4 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.1011-37379G>A		intron_variant	Intron 5 of 14		NP_001400921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1011-37379G>A		intron_variant	Intron 4 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.1011-37379G>A		intron_variant	Intron 5 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000714048.1	n.1011-37379G>A		intron_variant	Intron 4 of 12			ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51157 AN: 151578 Hom.: 8892 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.305

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

GnomAD4 genome AF: 0.338 AC: 51216 AN: 151696 Hom.: 8909 Cov.: 32 AF XY: 0.336 AC XY: 24928 AN XY: 74136

African (AFR) AF: 0.346 AC: 14321 AN: 41424

American (AMR) AF: 0.273 AC: 4148 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1325 AN: 3460

East Asian (EAS) AF: 0.185 AC: 951 AN: 5130

South Asian (SAS) AF: 0.275 AC: 1324 AN: 4812

European-Finnish (FIN) AF: 0.398 AC: 4207 AN: 10560

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23865 AN: 67782

Other (OTH) AF: 0.308 AC: 650 AN: 2112

Alfa AF: 0.340 Hom.: 16632

Bravo AF: 0.324

Asia WGS AF: 0.263 AC: 918 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.45
PhyloP100		-0.017
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: rs2284411; hg19: chr12-13866172;