chr12-13962548-C-T

Variant names:

• chr12-13962548-C-T
• rs4764043
• NM_000834.5:c.-19+17380G>A

Variant summary

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

The ENST00000609686.4(GRIN2B):​c.-19+17380G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 152,310 control chromosomes in the GnomAD database, including 264 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 0.050 (264 hom., cov: 32)
• Consequence: GRIN2B ENST00000609686.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 13 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000609686.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	NM_000834.5	MANE Select	c.-19+17380G>A		intron	N/A	NP_000825.2
	GRIN2B	NM_001413992.1		c.-19+17380G>A		intron	N/A	NP_001400921.1
	GRIN2B	NM_001413993.1		c.-19+18794G>A		intron	N/A	NP_001400922.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.-19+17380G>A		intron	N/A	ENSP00000477455.1
	GRIN2B	ENST00000630791.3	TSL:5	c.-19+17380G>A		intron	N/A	ENSP00000486677.3
	GRIN2B	ENST00000627535.2	TSL:5	c.-19+17380G>A		intron	N/A	ENSP00000486411.1

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7541 AN: 152192 Hom.: 267 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.0896

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0435

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

GnomAD4 genome AF: 0.0495 AC: 7543 AN: 152310 Hom.: 264 Cov.: 32 AF XY: 0.0492 AC XY: 3663 AN XY: 74482

African (AFR) AF: 0.0130 AC: 539 AN: 41566

American (AMR) AF: 0.0374 AC: 573 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3468

East Asian (EAS) AF: 0.0892 AC: 462 AN: 5180

South Asian (SAS) AF: 0.0615 AC: 297 AN: 4826

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0711 AC: 4839 AN: 68028

Other (OTH) AF: 0.0463 AC: 98 AN: 2116

Alfa AF: 0.0623 Hom.: 1105

Bravo AF: 0.0452

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.014
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: rs4764043; hg19: chr12-14115482;