12-13956753-G-A

Variant names:

• chr12-13956753-G-A
• rs219931
• NM_000834.5:c.-19+23175C>T

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+23175C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 152,040 control chromosomes in the GnomAD database, including 44,920 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 0.76 (44920 hom., cov: 31)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 7 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.848 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.-19+23175C>T		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.-19+23175C>T		intron	N/A	NP_001400921.1
	GRIN2B	NM_001413993.1		c.-19+24589C>T		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.-19+23175C>T		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.-19+23175C>T		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000627535.2	TSL:5	c.-19+23175C>T		intron	N/A	ENSP00000486411.1

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115838 AN: 151922 Hom.: 44898 Cov.: 31

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.854

Gnomad OTH AF: 0.756

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

GnomAD4 genome AF: 0.762 AC: 115921 AN: 152040 Hom.: 44920 Cov.: 31 AF XY: 0.756 AC XY: 56182 AN XY: 74316

African (AFR) AF: 0.664 AC: 27550 AN: 41460

American (AMR) AF: 0.650 AC: 9926 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2682 AN: 3468

East Asian (EAS) AF: 0.584 AC: 3005 AN: 5144

South Asian (SAS) AF: 0.771 AC: 3713 AN: 4814

European-Finnish (FIN) AF: 0.787 AC: 8305 AN: 10556

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.854 AC: 58087 AN: 68006

Other (OTH) AF: 0.755 AC: 1591 AN: 2108

Alfa AF: 0.827 Hom.: 38277

Bravo AF: 0.743

Asia WGS AF: 0.670 AC: 2330 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.9
DANN	Benign	0.82
PhyloP100		0.51
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: rs219931; hg19: chr12-14109687;