rs2300238

Variant names:

• chr12-13660396-C-T
• rs2300238
• NM_000834.5:c.1125+15349G>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.1125+15349G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,888 control chromosomes in the GnomAD database, including 12,885 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 0.41 (12885 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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 (AMR) allele frequency at 95% confidence interval = 0.449 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.1125+15349G>A		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.1125+15349G>A		intron	N/A	NP_001400921.1	A0A8D9PHB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.1125+15349G>A		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.1125+15349G>A		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000636855.1	TSL:5	n.23+15349G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61851 AN: 151770 Hom.: 12871 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.408 AC: 61895 AN: 151888 Hom.: 12885 Cov.: 32 AF XY: 0.400 AC XY: 29716 AN XY: 74218

African (AFR) AF: 0.439 AC: 18164 AN: 41406

American (AMR) AF: 0.458 AC: 6992 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1324 AN: 3470

East Asian (EAS) AF: 0.184 AC: 948 AN: 5152

South Asian (SAS) AF: 0.353 AC: 1699 AN: 4808

European-Finnish (FIN) AF: 0.305 AC: 3214 AN: 10542

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28188 AN: 67938

Other (OTH) AF: 0.413 AC: 869 AN: 2104

Alfa AF: 0.418 Hom.: 41590

Bravo AF: 0.422

Asia WGS AF: 0.285 AC: 992 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	5.7
DANN	Benign	0.71
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2300238;

hg19: chr12-13813330;