12-13716791-G-T

Variant names:

• chr12-13716791-G-T
• rs2268115
• NM_000834.5:c.1010+36526C>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+36526C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 151,642 control chromosomes in the GnomAD database, including 24,233 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 0.56 (24233 hom., cov: 31)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• Publications: 12 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1010+36526C>A		intron_variant	Intron 4 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.1010+36526C>A		intron_variant	Intron 5 of 14		NP_001400921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1010+36526C>A		intron_variant	Intron 4 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.1010+36526C>A		intron_variant	Intron 5 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000714048.1	n.1010+36526C>A		intron_variant	Intron 4 of 12			ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85037 AN: 151524 Hom.: 24188 Cov.: 31

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.537

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

GnomAD4 genome AF: 0.561 AC: 85138 AN: 151642 Hom.: 24233 Cov.: 31 AF XY: 0.557 AC XY: 41277 AN XY: 74068

African (AFR) AF: 0.638 AC: 26445 AN: 41418

American (AMR) AF: 0.496 AC: 7546 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2134 AN: 3468

East Asian (EAS) AF: 0.366 AC: 1867 AN: 5108

South Asian (SAS) AF: 0.492 AC: 2367 AN: 4814

European-Finnish (FIN) AF: 0.552 AC: 5823 AN: 10550

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37111 AN: 67760

Other (OTH) AF: 0.538 AC: 1133 AN: 2106

Alfa AF: 0.527 Hom.: 6370

Bravo AF: 0.555

Asia WGS AF: 0.457 AC: 1590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.0
DANN	Benign	0.12
PhyloP100		0.37
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: rs2268115; hg19: chr12-13869725;