12-13561429-G-T

Variant names:

• chr12-13561429-G-T
• rs1805476
• NM_000834.5:c.*1354C>A

Variant summary

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

The NM_000834.5(GRIN2B):​c.*1354C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,204 control chromosomes in the GnomAD database, including 10,456 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 0.34 (10404 hom., cov: 30)
  • Exomes 𝑓: 0.47 (52 hom.)
• Consequence: GRIN2B NM_000834.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.598
• Publications: 28 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.*1354C>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1	c.*1354C>A		3_prime_UTR_variant	Exon 15 of 15		NP_001400921.1
GRIN2B	XM_005253351.3	c.*1354C>A		3_prime_UTR_variant	Exon 4 of 4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.*1354C>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_000834.5	ENSP00000477455.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51560 AN: 151626 Hom.: 10400 Cov.: 30

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.467 AC: 214 AN: 458 Hom.: 52 Cov.: 0 AF XY: 0.486 AC XY: 134 AN XY: 276

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.486 AC: 205 AN: 422

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.286 AC: 8 AN: 28

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.340 AC: 51562 AN: 151746 Hom.: 10404 Cov.: 30 AF XY: 0.352 AC XY: 26083 AN XY: 74126

African (AFR) AF: 0.143 AC: 5904 AN: 41398

American (AMR) AF: 0.376 AC: 5729 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1541 AN: 3468

East Asian (EAS) AF: 0.803 AC: 4092 AN: 5098

South Asian (SAS) AF: 0.533 AC: 2551 AN: 4790

European-Finnish (FIN) AF: 0.469 AC: 4948 AN: 10542

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25644 AN: 67886

Other (OTH) AF: 0.367 AC: 776 AN: 2112

Alfa AF: 0.364 Hom.: 13942

Bravo AF: 0.325

Asia WGS AF: 0.623 AC: 2163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.31
DANN	Benign	0.32
PhyloP100		-0.60
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: rs1805476; hg19: chr12-13714363;