rs220599

Variant names:

• chr12-13822364-G-A
• rs220599
• NM_000834.5:c.411+43434C>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.411+43434C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 151,902 control chromosomes in the GnomAD database, including 11,854 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 0.39 (11854 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 17 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 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.411+43434C>T		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.411+43434C>T		intron	N/A	NP_001400921.1
	GRIN2B	NM_001413993.1		c.411+43434C>T		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.411+43434C>T		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.411+43434C>T		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000714048.1		n.411+43434C>T		intron	N/A	ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58956 AN: 151784 Hom.: 11832 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.389 AC: 59017 AN: 151902 Hom.: 11854 Cov.: 32 AF XY: 0.387 AC XY: 28723 AN XY: 74234

African (AFR) AF: 0.463 AC: 19182 AN: 41430

American (AMR) AF: 0.448 AC: 6846 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3470

East Asian (EAS) AF: 0.537 AC: 2778 AN: 5178

South Asian (SAS) AF: 0.330 AC: 1587 AN: 4812

European-Finnish (FIN) AF: 0.329 AC: 3467 AN: 10534

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23029 AN: 67894

Other (OTH) AF: 0.365 AC: 769 AN: 2104

Alfa AF: 0.354 Hom.: 6994

Bravo AF: 0.405

Asia WGS AF: 0.405 AC: 1406 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.60
PhyloP100		-0.023
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: rs220599; hg19: chr12-13975298; COSMIC: COSV74204719;