rs45600931

chr12-13563740-G-Achr12-13563740-G-Cchr12-13563740-G-T

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.3498C>T(p.Ser1166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00724 in 1,613,862 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (57 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.55

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-13563740-G-A is Benign according to our data. Variant chr12-13563740-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13563740-G-A is described in Lovd as [Likely_benign]. Variant chr12-13563740-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00519 (791/152268) while in subpopulation NFE AF= 0.00779 (530/68018). AF 95% confidence interval is 0.00724. There are 3 homozygotes in gnomad4. There are 390 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 790 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.3498C>T	p.Ser1166=	synonymous_variant	14/14	ENST00000609686.4
GRIN2B	NM_001413992.1	c.3498C>T	p.Ser1166=	synonymous_variant	15/15
GRIN2B	XM_005253351.3	c.1284C>T	p.Ser428=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.3498C>T	p.Ser1166=	synonymous_variant	14/14	1	NM_000834.5	P1
GRIN2B	ENST00000637214.1	c.69+44863C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 790 AN: 152150 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00778

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00602 AC: 1509 AN: 250582 Hom.: 8 AF XY: 0.00603 AC XY: 817 AN XY: 135466

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00851

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00745 AC: 10891 AN: 1461594 Hom.: 57 Cov.: 37 AF XY: 0.00737 AC XY: 5356 AN XY: 727100

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00429

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.00831

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.00519 AC: 791 AN: 152268 Hom.: 3 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74456

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00503 Hom.: 2

Bravo AF: 0.00467

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 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. -

Intellectual disability, autosomal dominant 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

GRIN2B: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.9
Dann	Benign	0.76

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: rs45600931; hg19: chr12-13716674;