rs220549

Variant names:

• chr12-13784386-T-C
• rs220549
• NM_000834.5:c.412-30471A>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.412-30471A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 151,746 control chromosomes in the GnomAD database, including 23,008 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 0.54 (23008 hom., cov: 30)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 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.412-30471A>G		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.412-30471A>G		intron	N/A	NP_001400921.1
	GRIN2B	NM_001413993.1		c.412-30471A>G		intron	N/A	NP_001400922.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.412-30471A>G		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.412-30471A>G		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000714048.1		n.412-30471A>G		intron	N/A	ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81760 AN: 151628 Hom.: 23001 Cov.: 30

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.539 AC: 81791 AN: 151746 Hom.: 23008 Cov.: 30 AF XY: 0.549 AC XY: 40717 AN XY: 74158

African (AFR) AF: 0.371 AC: 15365 AN: 41370

American (AMR) AF: 0.643 AC: 9802 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1645 AN: 3470

East Asian (EAS) AF: 0.806 AC: 4146 AN: 5146

South Asian (SAS) AF: 0.705 AC: 3385 AN: 4800

European-Finnish (FIN) AF: 0.657 AC: 6900 AN: 10502

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.572 AC: 38843 AN: 67912

Other (OTH) AF: 0.553 AC: 1162 AN: 2102

Alfa AF: 0.563 Hom.: 53457

Bravo AF: 0.530

Asia WGS AF: 0.702 AC: 2438 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.5
DANN	Benign	0.57
PhyloP100		0.54
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: rs220549; hg19: chr12-13937320;