12-13562374-A-C

Position:

• chr12-13562374-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000834.5(GRIN2B):​c.*409T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 199,382 control chromosomes in the GnomAD database, including 17,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13159 hom., cov: 32)
  • Exomes 𝑓: 0.42 (4765 hom.)
• Consequence: GRIN2B NM_000834.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-13562374-A-C is Benign according to our data. Variant chr12-13562374-A-C is described in ClinVar as [Benign]. Clinvar id is 1281683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.*409T>G		3_prime_UTR_variant	14/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.*409T>G		3_prime_UTR_variant	15/15
GRIN2B	XM_005253351.3	c.*409T>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.*409T>G		3_prime_UTR_variant	14/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+46229T>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57427 AN: 151944 Hom.: 13156 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.424 AC: 20070 AN: 47320 Hom.: 4765 Cov.: 0 AF XY: 0.421 AC XY: 10003 AN XY: 23770

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.477

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.407

Gnomad4 NFE exome AF: 0.473

Gnomad4 OTH exome AF: 0.441

GnomAD4 genome AF: 0.378 AC: 57432 AN: 152062 Hom.: 13159 Cov.: 32 AF XY: 0.375 AC XY: 27860 AN XY: 74312

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.513

Gnomad4 OTH AF: 0.436

Alfa AF: 0.492 Hom.: 32149

Bravo AF: 0.374

Asia WGS AF: 0.250 AC: 872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2021	This variant is associated with the following publications: (PMID: 26257337) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs890; hg19: chr12-13715308;