rs219873

Variant names:

• chr12-13923512-G-A
• rs219873
• NM_000834.5:c.-19+56416C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-13923512-G-A
• chr12-13923512-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000834.5(GRIN2B):​c.-19+56416C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 152,050 control chromosomes in the GnomAD database, including 44,237 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 0.75 (44237 hom., cov: 31)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.849 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+56416C>T		intron	N/A	NP_000825.2	Q13224
	GRIN2B	NM_001413992.1		c.-19+56416C>T		intron	N/A	NP_001400921.1	A0A8D9PHB2
	GRIN2B	NM_001413993.1		c.-18-57286C>T		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+56416C>T		intron	N/A	ENSP00000477455.1	Q13224
	GRIN2B	ENST00000630791.3	TSL:5	c.-19+56416C>T		intron	N/A	ENSP00000486677.3	A0A0D9SFK0
	GRIN2B	ENST00000627535.2	TSL:5	c.-19+56416C>T		intron	N/A	ENSP00000486411.1	A0A0D9SFA0

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114697 AN: 151930 Hom.: 44212 Cov.: 31

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.752

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

GnomAD4 genome AF: 0.755 AC: 114781 AN: 152050 Hom.: 44237 Cov.: 31 AF XY: 0.750 AC XY: 55709 AN XY: 74322

African (AFR) AF: 0.637 AC: 26385 AN: 41426

American (AMR) AF: 0.648 AC: 9904 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 2732 AN: 3468

East Asian (EAS) AF: 0.573 AC: 2959 AN: 5168

South Asian (SAS) AF: 0.781 AC: 3755 AN: 4810

European-Finnish (FIN) AF: 0.783 AC: 8283 AN: 10578

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.855 AC: 58121 AN: 68006

Other (OTH) AF: 0.751 AC: 1587 AN: 2114

Alfa AF: 0.802 Hom.: 6155

Bravo AF: 0.735

Asia WGS AF: 0.680 AC: 2367 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.72
PhyloP100		0.94
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: rs219873; hg19: chr12-14076446;