chr12-13681879-T-C

Variant names:

• chr12-13681879-T-C
• rs10492133
• NM_000834.5:c.1011-6020A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000834.5(GRIN2B):​c.1011-6020A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,080 control chromosomes in the GnomAD database, including 2,375 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 0.17 (2375 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0450
• 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: 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1011-6020A>G		intron_variant	Intron 4 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.1011-6020A>G		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.1011-6020A>G		intron_variant	Intron 4 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.1011-6020A>G		intron_variant	Intron 5 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000714048.1	n.1011-6020A>G		intron_variant	Intron 4 of 12			ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26003 AN: 151962 Hom.: 2376 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.144

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

GnomAD4 genome AF: 0.171 AC: 26025 AN: 152080 Hom.: 2375 Cov.: 32 AF XY: 0.174 AC XY: 12931 AN XY: 74340

African (AFR) AF: 0.124 AC: 5142 AN: 41520

American (AMR) AF: 0.174 AC: 2655 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3472

East Asian (EAS) AF: 0.177 AC: 917 AN: 5176

South Asian (SAS) AF: 0.208 AC: 1002 AN: 4808

European-Finnish (FIN) AF: 0.248 AC: 2613 AN: 10552

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12974 AN: 67958

Other (OTH) AF: 0.143 AC: 301 AN: 2110

Alfa AF: 0.182 Hom.: 319

Bravo AF: 0.162

Asia WGS AF: 0.177 AC: 613 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.69
PhyloP100		0.045
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: rs10492133; hg19: chr12-13834813;