rs1019385

Positions:

• chr12-13981909-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001413992.1(GRIN2B):​c.-683+7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 153,050 control chromosomes in the GnomAD database, including 13,168 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 0.38 (13015 hom., cov: 29)
  • Exomes 𝑓: 0.45 (153 hom.)
• Consequence: GRIN2B NM_001413992.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.835

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2B	NM_001413992.1	c.-683+7G>T		splice_region_variant, intron_variant			NP_001400921.1
GRIN2B	NM_001413993.1	c.-254+7G>T		splice_region_variant, intron_variant			NP_001400922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000630791.2	c.-683+7G>T		splice_region_variant, intron_variant		5		ENSP00000486677.3
GRIN2B	ENST00000627535.2	c.-448+7G>T		splice_region_variant, intron_variant		5		ENSP00000486411.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57319 AN: 151406 Hom.: 13018 Cov.: 29

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.411

GnomAD4 exome AF: 0.450 AC: 689 AN: 1532 Hom.: 153 Cov.: 0 AF XY: 0.467 AC XY: 387 AN XY: 828

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.714

Gnomad4 ASJ exome AF: 0.700

Gnomad4 EAS exome AF: 0.534

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.449

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.378 AC: 57320 AN: 151518 Hom.: 13015 Cov.: 29 AF XY: 0.384 AC XY: 28391 AN XY: 73980

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.562

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.412

Alfa AF: 0.405 Hom.: 1807

Bravo AF: 0.378

Asia WGS AF: 0.515 AC: 1795 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1019385; hg19: chr12-14134843; COSMIC: COSV74205295;