rs1531228

Variant names:

• chr12-13476447-C-T
• rs1531228
• ENST00000637214.1:c.70-38436G>A

Variant summary

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

The ENST00000637214.1(GRIN2B):​c.70-38436G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 152,076 control chromosomes in the GnomAD database, including 2,079 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 0.16 (2079 hom., cov: 32)
• Consequence: GRIN2B ENST00000637214.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 1 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 (AMR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000637214.1	c.70-38436G>A		intron_variant	Intron 1 of 1	5		ENSP00000489997.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24710 AN: 151958 Hom.: 2072 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.163 AC: 24746 AN: 152076 Hom.: 2079 Cov.: 32 AF XY: 0.169 AC XY: 12531 AN XY: 74306

African (AFR) AF: 0.180 AC: 7461 AN: 41478

American (AMR) AF: 0.223 AC: 3405 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3468

East Asian (EAS) AF: 0.116 AC: 595 AN: 5142

South Asian (SAS) AF: 0.184 AC: 886 AN: 4816

European-Finnish (FIN) AF: 0.191 AC: 2015 AN: 10558

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9602 AN: 68004

Other (OTH) AF: 0.146 AC: 309 AN: 2112

Alfa AF: 0.148 Hom.: 3079

Bravo AF: 0.163

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.10
DANN	Benign	0.61
PhyloP100		-1.9

Splicing

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

Other links and lift over

dbSNP: rs1531228; hg19: chr12-13629381;