12-13634912-T-C

Variant names:

• chr12-13634912-T-C
• rs2160519
• NM_000834.5:c.1126-18255A>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.1126-18255A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 152,336 control chromosomes in the GnomAD database, including 217 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 0.035 (217 hom., cov: 32)
• Consequence: GRIN2B NM_000834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1126-18255A>G		intron_variant	Intron 5 of 13	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.1126-18255A>G		intron_variant	Intron 6 of 14		NP_001400921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1126-18255A>G		intron_variant	Intron 5 of 13	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.3	c.1126-18255A>G		intron_variant	Intron 6 of 14	5		ENSP00000486677.3
GRIN2B	ENST00000636855.1	n.24-660A>G		intron_variant	Intron 1 of 1	5
GRIN2B	ENST00000714048.1	n.1126-18255A>G		intron_variant	Intron 5 of 12			ENSP00000519339.1

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5348 AN: 152218 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.00567

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0498

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0325

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

GnomAD4 genome AF: 0.0350 AC: 5337 AN: 152336 Hom.: 217 Cov.: 32 AF XY: 0.0405 AC XY: 3019 AN XY: 74478

African (AFR) AF: 0.00565 AC: 235 AN: 41592

American (AMR) AF: 0.0229 AC: 351 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 173 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1037 AN: 5178

South Asian (SAS) AF: 0.110 AC: 532 AN: 4824

European-Finnish (FIN) AF: 0.103 AC: 1096 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1816 AN: 68030

Other (OTH) AF: 0.0331 AC: 70 AN: 2116

Alfa AF: 0.0322 Hom.: 530

Bravo AF: 0.0273

Asia WGS AF: 0.135 AC: 467 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.12
DANN	Benign	0.38
PhyloP100		-1.4
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: rs2160519; hg19: chr12-13787846;