rs220573

Variant names:

• chr12-13803800-G-A
• rs220573
• NM_000834.5:c.412-49885C>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.412-49885C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 151,904 control chromosomes in the GnomAD database, including 11,434 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 0.38 (11434 hom., cov: 31)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 10 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 = 0.532 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	NM_000834.5	MANE Select	c.412-49885C>T		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.412-49885C>T		intron	N/A	NP_001400921.1	A0A8D9PHB2
	GRIN2B	NM_001413993.1		c.412-49885C>T		intron	N/A	NP_001400922.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.412-49885C>T		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.412-49885C>T		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000714048.1		n.412-49885C>T		intron	N/A	ENSP00000519339.1	A0AAQ5BH89

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58274 AN: 151786 Hom.: 11421 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.384 AC: 58321 AN: 151904 Hom.: 11434 Cov.: 31 AF XY: 0.383 AC XY: 28425 AN XY: 74190

African (AFR) AF: 0.430 AC: 17803 AN: 41418

American (AMR) AF: 0.448 AC: 6840 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 893 AN: 3468

East Asian (EAS) AF: 0.548 AC: 2831 AN: 5162

South Asian (SAS) AF: 0.369 AC: 1772 AN: 4806

European-Finnish (FIN) AF: 0.340 AC: 3582 AN: 10544

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.344 AC: 23404 AN: 67940

Other (OTH) AF: 0.364 AC: 768 AN: 2110

Alfa AF: 0.357 Hom.: 31547

Bravo AF: 0.397

Asia WGS AF: 0.419 AC: 1458 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	0.37
DANN	Benign	0.48
PhyloP100		-1.0
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: rs220573; hg19: chr12-13956734;