12-13934665-C-T

Variant names:

• chr12-13934665-C-T
• rs219892
• NM_000834.5:c.-19+45263G>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.-19+45263G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 150,154 control chromosomes in the GnomAD database, including 46,623 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 0.78 (46623 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206
• Publications: 5 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.852 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.-19+45263G>A		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.-19+45263G>A		intron	N/A	NP_001400921.1	A0A8D9PHB2
	GRIN2B	NM_001413993.1		c.-19+46677G>A		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.-19+45263G>A		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.-19+45263G>A		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000627535.2	TSL:5	c.-19+45263G>A		intron	N/A	ENSP00000486411.1	A0A0D9SFA0

Frequencies

GnomAD3 genomes AF: 0.778 AC: 116672 AN: 150034 Hom.: 46597 Cov.: 32

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.771

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

GnomAD4 genome AF: 0.778 AC: 116758 AN: 150154 Hom.: 46623 Cov.: 32 AF XY: 0.771 AC XY: 56627 AN XY: 73468

African (AFR) AF: 0.706 AC: 27962 AN: 39618

American (AMR) AF: 0.658 AC: 10019 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2739 AN: 3472

East Asian (EAS) AF: 0.576 AC: 2961 AN: 5140

South Asian (SAS) AF: 0.780 AC: 3764 AN: 4826

European-Finnish (FIN) AF: 0.787 AC: 8328 AN: 10588

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58314 AN: 67998

Other (OTH) AF: 0.770 AC: 1606 AN: 2086

Alfa AF: 0.818 Hom.: 130579

Bravo AF: 0.742

Asia WGS AF: 0.678 AC: 2358 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.75
PhyloP100		0.21
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: rs219892; hg19: chr12-14087599;