rs1805482

chr12-13611840-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000834.5(GRIN2B):c.1665C>T(p.Ser555=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,612,232 control chromosomes in the GnomAD database, including 80,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5876 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74317 hom.)
• Consequence: GRIN2B NM_000834.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0260

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-13611840-G-A is Benign according to our data. Variant chr12-13611840-G-A is described in ClinVar as [Benign]. Clinvar id is 129200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13611840-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.026 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2B	NM_000834.5	c.1665C>T	p.Ser555=	synonymous_variant	9/14	ENST00000609686.4
LOC105369668	XR_001749013.2	n.484+1240G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2B	ENST00000609686.4	c.1665C>T	p.Ser555=	synonymous_variant	9/14	1	NM_000834.5	P1
	ENST00000652867.1	n.203-3258G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39848 AN: 152026 Hom.: 5866 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.294

GnomAD3 exomes AF: 0.271 AC: 68162 AN: 251368 Hom.: 10732 AF XY: 0.269 AC XY: 36530 AN XY: 135860

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.0122

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.310 AC: 452145 AN: 1460088 Hom.: 74317 Cov.: 33 AF XY: 0.305 AC XY: 221855 AN XY: 726446

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.339

Gnomad4 OTH exome AF: 0.295

GnomAD4 genome AF: 0.262 AC: 39873 AN: 152144 Hom.: 5876 Cov.: 32 AF XY: 0.254 AC XY: 18879 AN XY: 74372

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.294

Alfa AF: 0.324 Hom.: 16499

Bravo AF: 0.276

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 6 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 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

- -

Developmental and epileptic encephalopathy, 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.1
Dann	Benign	0.63

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: rs1805482; hg19: chr12-13764774; COSMIC: COSV74206213; COSMIC: COSV74206213;