rs1805482

Positions:

chr12-13611840-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000834.5(GRIN2B):c.1665C>T(p.Ser555Ser) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0260

Variant links:

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 links:

ENSG00000287928 (HGNC:):

ENSG00000287928 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
GRIN2B	NM_000834.5 linkuse as main transcript	c.1665C>T	p.Ser555Ser	synonymous_variant	9/14	ENST00000609686.4	NP_000825.2	Q13224A0A8D9PHB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4 linkuse as main transcript	c.1665C>T	p.Ser555Ser	synonymous_variant	9/14	1	NM_000834.5	ENSP00000477455.1		Q13224
ENSG00000287928	ENST00000652867.1 linkuse as main transcript	n.203-3258G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39848

AN:

152026

Hom.:

5866

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.305

AC XY:

221855

AN XY:

726446

show subpopulations

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.:

AF XY:

0.254

AC XY:

18879

AN XY:

74372

show subpopulations

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 60. Only high quality variants are reported. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Intellectual disability, autosomal dominant 6

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
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	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over