12-13865843-G-C

Position:

chr12-13865843-G-C

Variant summary

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

The NM_000834.5(GRIN2B):c.366C>G(p.Pro122Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,612,878 control chromosomes in the GnomAD database, including 136,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13790 hom., cov: 31)

Exomes 𝑓: 0.41 ( 123036 hom. )

Consequence

GRIN2B
NM_000834.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.94

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:

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=-0.51).

BP6

Variant 12-13865843-G-C is Benign according to our data. Variant chr12-13865843-G-C is described in ClinVar as [Benign]. Clinvar id is 129205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13865843-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.94 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.483 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.366C>G	p.Pro122Pro	synonymous_variant	3/14	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.366C>G	p.Pro122Pro	synonymous_variant	3/14	1	NM_000834.5	ENSP00000477455.1		Q13224
GRIN2B	ENST00000630791.2 linkuse as main transcript	c.366C>G	p.Pro122Pro	synonymous_variant	4/8	5		ENSP00000486677.3		A0A0D9SFK0

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63823

AN:

151732

Hom.:

13774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.201

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.497

Gnomad FIN

AF:

0.395

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.394

GnomAD3 exomes

AF:

0.408

AC:

102530

AN:

251152

Hom.:

21587

AF XY:

0.413

AC XY:

56114

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.375

Gnomad EAS exome

AF:

0.491

Gnomad SAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.402

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.389

GnomAD4 exome

AF:

0.408

AC:

596152

AN:

1461028

Hom.:

123036

Cov.:

AF XY:

0.411

AC XY:

298613

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.489

Gnomad4 AMR exome

AF:

0.304

Gnomad4 ASJ exome

AF:

0.379

Gnomad4 EAS exome

AF:

0.470

Gnomad4 SAS exome

AF:

0.495

Gnomad4 FIN exome

AF:

0.407

Gnomad4 NFE exome

AF:

0.402

Gnomad4 OTH exome

AF:

0.413

GnomAD4 genome

AF:

0.421

AC:

63881

AN:

151850

Hom.:

13790

Cov.:

AF XY:

0.421

AC XY:

31253

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.488

Gnomad4 AMR

AF:

0.343

Gnomad4 ASJ

AF:

0.401

Gnomad4 EAS

AF:

0.475

Gnomad4 SAS

AF:

0.496

Gnomad4 FIN

AF:

0.395

Gnomad4 NFE

AF:

0.397

Gnomad4 OTH

AF:

0.394

Alfa

AF:

0.400

Hom.:

3958

Bravo

AF:

0.418

Asia WGS

AF:

0.488

AC:

1697

AN:

3478

EpiCase

AF:

0.388

EpiControl

AF:

0.389

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2013	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. -
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 44% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 41. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2017	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Intellectual disability, autosomal dominant 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

-0.51

CADD

Benign

5.3

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