rs35025065

Positions:

• chr12-13615652-G-A
• chr12-13615652-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000834.5(GRIN2B):​c.1341C>T​(p.Asp447Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,612,414 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (88 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.223

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]

ENSG00000287928 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-13615652-G-A is Benign according to our data. Variant chr12-13615652-G-A is described in ClinVar as [Benign]. Clinvar id is 98440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.223 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00852 (1296/152108) while in subpopulation NFE AF= 0.0109 (738/67992). AF 95% confidence interval is 0.0102. There are 3 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1296 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2B	NM_000834.5	c.1341C>T	p.Asp447Asp	synonymous_variant	7/14	ENST00000609686.4	NP_000825.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1341C>T	p.Asp447Asp	synonymous_variant	7/14	1	NM_000834.5	ENSP00000477455.1
GRIN2B	ENST00000630791.2	c.1341C>T	p.Asp447Asp	synonymous_variant	8/8	5		ENSP00000486677.3
ENSG00000287928	ENST00000652867.1	n.331+426G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00853 AC: 1296 AN: 151990 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00911

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00654 AC: 1642 AN: 251026 Hom.: 18 AF XY: 0.00675 AC XY: 916 AN XY: 135782

Gnomad AFR exome AF: 0.00906

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00975

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00895 AC: 13070 AN: 1460306 Hom.: 88 Cov.: 31 AF XY: 0.00880 AC XY: 6394 AN XY: 726620

Gnomad4 AFR exome AF: 0.00891

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.00459

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00882

GnomAD4 genome AF: 0.00852 AC: 1296 AN: 152108 Hom.: 3 Cov.: 32 AF XY: 0.00821 AC XY: 610 AN XY: 74334

Gnomad4 AFR AF: 0.00908

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00416

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00948 Hom.: 4

Bravo AF: 0.00851

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0103

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2017	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Psychiatry Genetics Yale University	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GRIN2B: BP4, BP7, BS1, BS2 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

GRIN2B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.9
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs35025065; hg19: chr12-13768586;