12-13570458-T-G

Variant names:

• chr12-13570458-T-G
• rs1806195
• NM_000834.5:c.2172-441A>C

Variant summary

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

The NM_000834.5(GRIN2B):​c.2172-441A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 152,052 control chromosomes in the GnomAD database, including 20,942 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 0.51 (20942 hom., cov: 33)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• 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: 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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.2172-441A>C		intron_variant	Intron 11 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.2172-441A>C		intron_variant	Intron 12 of 14		NP_001400921.1
GRIN2B	XM_005253351.3	c.-43-441A>C		intron_variant	Intron 1 of 3		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.2172-441A>C		intron_variant	Intron 11 of 13	1	NM_000834.5	ENSP00000477455.1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78170 AN: 151934 Hom.: 20915 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.528

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

GnomAD4 genome AF: 0.515 AC: 78238 AN: 152052 Hom.: 20942 Cov.: 33 AF XY: 0.525 AC XY: 38992 AN XY: 74334

African (AFR) AF: 0.470 AC: 19506 AN: 41472

American (AMR) AF: 0.507 AC: 7745 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1870 AN: 3468

East Asian (EAS) AF: 0.985 AC: 5091 AN: 5170

South Asian (SAS) AF: 0.755 AC: 3638 AN: 4818

European-Finnish (FIN) AF: 0.570 AC: 6032 AN: 10574

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.481 AC: 32691 AN: 67954

Other (OTH) AF: 0.530 AC: 1117 AN: 2108

Alfa AF: 0.408 Hom.: 1745

Bravo AF: 0.506

Asia WGS AF: 0.825 AC: 2865 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		1.2
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: rs1806195; hg19: chr12-13723392;