12-13774962-C-T

Variant names:

• chr12-13774962-C-T
• rs6488619
• NM_000834.5:c.412-21047G>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.412-21047G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 152,124 control chromosomes in the GnomAD database, including 52,338 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 0.83 (52338 hom., cov: 31)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.311
• 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: 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 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.412-21047G>A		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.412-21047G>A		intron	N/A	NP_001400921.1
	GRIN2B	NM_001413993.1		c.412-21047G>A		intron	N/A	NP_001400922.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.412-21047G>A		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.412-21047G>A		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000714048.1		n.412-21047G>A		intron	N/A	ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125611 AN: 152006 Hom.: 52283 Cov.: 31

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.883

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.777

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.807

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

GnomAD4 genome AF: 0.826 AC: 125727 AN: 152124 Hom.: 52338 Cov.: 31 AF XY: 0.821 AC XY: 61033 AN XY: 74354

African (AFR) AF: 0.916 AC: 38027 AN: 41506

American (AMR) AF: 0.868 AC: 13270 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2437 AN: 3468

East Asian (EAS) AF: 0.856 AC: 4412 AN: 5154

South Asian (SAS) AF: 0.777 AC: 3746 AN: 4824

European-Finnish (FIN) AF: 0.726 AC: 7678 AN: 10580

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.786 AC: 53453 AN: 67984

Other (OTH) AF: 0.808 AC: 1704 AN: 2110

Alfa AF: 0.803 Hom.: 163491

Bravo AF: 0.843

Asia WGS AF: 0.835 AC: 2903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.4
DANN	Benign	0.30
PhyloP100		0.31
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: rs6488619; hg19: chr12-13927896;