NM_000834.5:c.1010+33617T>A

Variant names:

• chr12-13719700-A-T
• rs2268119
• NM_000834.5:c.1010+33617T>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.1010+33617T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,028 control chromosomes in the GnomAD database, including 3,856 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 0.21 (3856 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.389
• Publications: 8 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 = 0.47 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.1010+33617T>A		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.1010+33617T>A		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.1010+33617T>A		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.1010+33617T>A		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000714048.1		n.1010+33617T>A		intron	N/A	ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32432 AN: 151910 Hom.: 3844 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.214 AC: 32470 AN: 152028 Hom.: 3856 Cov.: 32 AF XY: 0.222 AC XY: 16495 AN XY: 74282

African (AFR) AF: 0.169 AC: 7029 AN: 41520

American (AMR) AF: 0.186 AC: 2842 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2490 AN: 5124

South Asian (SAS) AF: 0.348 AC: 1672 AN: 4808

European-Finnish (FIN) AF: 0.276 AC: 2911 AN: 10562

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.203 AC: 13783 AN: 67962

Other (OTH) AF: 0.225 AC: 476 AN: 2112

Alfa AF: 0.207 Hom.: 426

Bravo AF: 0.201

Asia WGS AF: 0.415 AC: 1439 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	1.7
DANN	Benign	0.21
PhyloP100		-0.39
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: rs2268119; hg19: chr12-13872634;