12-13866194-C-T

Position:

chr12-13866194-C-T

Variant summary

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

The NM_000834.5(GRIN2B):c.15G>A(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,609,162 control chromosomes in the GnomAD database, including 1,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 200 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1734 hom. )

Consequence

GRIN2B
NM_000834.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.0290

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 12-13866194-C-T is Benign according to our data. Variant chr12-13866194-C-T is described in ClinVar as [Benign]. Clinvar id is 98442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13866194-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.029 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2B	NM_000834.5 link	c.15G>A	p.Ala5Ala	synonymous_variant	3/14	ENST00000609686.4	NP_000825.2	Q13224A0A8D9PHB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRIN2B	ENST00000609686.4 link	c.15G>A	p.Ala5Ala	synonymous_variant	3/14	1	NM_000834.5	ENSP00000477455.1	Q13224
GRIN2B	ENST00000630791.2 link	c.15G>A	p.Ala5Ala	synonymous_variant	4/8	5		ENSP00000486677.3	A0A0D9SFK0
GRIN2B	ENST00000627535.2 link	c.15G>A	p.Ala5Ala	synonymous_variant	3/3	5		ENSP00000486411.1	A0A0D9SFA0

Frequencies

GnomAD3 genomes

AF:

0.0351

AC:

5340

AN:

152086

Hom.:

201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.0947

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0384

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0489

AC:

11860

AN:

242460

Hom.:

500

AF XY:

0.0528

AC XY:

6969

AN XY:

131912

show subpopulations

Gnomad AFR exome

AF:

0.00755

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00354

Gnomad EAS exome

AF:

0.122

Gnomad SAS exome

AF:

0.0983

Gnomad FIN exome

AF:

0.0961

Gnomad NFE exome

AF:

0.0377

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0411

AC:

59901

AN:

1456956

Hom.:

1734

Cov.:

AF XY:

0.0431

AC XY:

31210

AN XY:

724858

show subpopulations

Gnomad4 AFR exome

AF:

0.00621

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.0939

Gnomad4 SAS exome

AF:

0.0975

Gnomad4 FIN exome

AF:

0.0927

Gnomad4 NFE exome

AF:

0.0359

Gnomad4 OTH exome

AF:

0.0417

GnomAD4 genome

AF:

0.0351

AC:

5338

AN:

152206

Hom.:

200

Cov.:

AF XY:

0.0396

AC XY:

2950

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00746

Gnomad4 AMR

AF:

0.0150

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.101

Gnomad4 FIN

AF:

0.0947

Gnomad4 NFE

AF:

0.0384

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.0317

Hom.:

Bravo

AF:

0.0257

Asia WGS

AF:

0.118

AC:

410

AN:

3478

EpiCase

AF:

0.0325

EpiControl

AF:

0.0287

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Psychiatry Genetics Yale University	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 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. -

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

-0.53

CADD

Benign

9.5

DANN

Benign

0.78

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