12-13815252-A-G

Variant names:

• chr12-13815252-A-G
• rs220597
• NM_000834.5:c.411+50546T>C

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+50546T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,948 control chromosomes in the GnomAD database, including 15,436 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 0.44 (15436 hom., cov: 31)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.244
• 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: 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 = 0.716 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.411+50546T>C		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.411+50546T>C		intron	N/A	NP_001400921.1	A0A8D9PHB2
	GRIN2B	NM_001413993.1		c.411+50546T>C		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.411+50546T>C		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.411+50546T>C		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000714048.1		n.411+50546T>C		intron	N/A	ENSP00000519339.1	A0AAQ5BH89

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66803 AN: 151830 Hom.: 15410 Cov.: 31

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.411

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

GnomAD4 genome AF: 0.440 AC: 66883 AN: 151948 Hom.: 15436 Cov.: 31 AF XY: 0.449 AC XY: 33304 AN XY: 74254

African (AFR) AF: 0.502 AC: 20825 AN: 41450

American (AMR) AF: 0.496 AC: 7566 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3472

East Asian (EAS) AF: 0.735 AC: 3792 AN: 5158

South Asian (SAS) AF: 0.509 AC: 2450 AN: 4816

European-Finnish (FIN) AF: 0.470 AC: 4946 AN: 10530

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24679 AN: 67936

Other (OTH) AF: 0.414 AC: 875 AN: 2112

Alfa AF: 0.388 Hom.: 50869

Bravo AF: 0.447

Asia WGS AF: 0.573 AC: 1989 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	2.7
DANN	Benign	0.52
PhyloP100		0.24
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: rs220597; hg19: chr12-13968186;