rs2270359

Variant names:

• chr12-13569379-A-C
• rs2270359
• NM_000834.5:c.2359+451T>G

Variant summary

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

The NM_000834.5(GRIN2B):​c.2359+451T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,034 control chromosomes in the GnomAD database, including 19,339 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 0.50 (19339 hom., cov: 33)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	NM_000834.5	MANE Select	c.2359+451T>G		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.2359+451T>G		intron	N/A	NP_001400921.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.2359+451T>G		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.2359+451T>G		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000637214.1	TSL:5	c.69+39224T>G		intron	N/A	ENSP00000489997.1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76037 AN: 151914 Hom.: 19307 Cov.: 33

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.516

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

GnomAD4 genome AF: 0.501 AC: 76123 AN: 152034 Hom.: 19339 Cov.: 33 AF XY: 0.497 AC XY: 36951 AN XY: 74306

African (AFR) AF: 0.543 AC: 22516 AN: 41436

American (AMR) AF: 0.532 AC: 8129 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1745 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1017 AN: 5168

South Asian (SAS) AF: 0.441 AC: 2127 AN: 4828

European-Finnish (FIN) AF: 0.444 AC: 4686 AN: 10544

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.503 AC: 34191 AN: 67986

Other (OTH) AF: 0.513 AC: 1083 AN: 2110

Alfa AF: 0.508 Hom.: 30651

Bravo AF: 0.511

Asia WGS AF: 0.340 AC: 1185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.5
DANN	Benign	0.83
PhyloP100		0.042
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: rs2270359; hg19: chr12-13722313;