chr12-13563041-A-G

Position:

chr12-13563041-A-G

Variant summary

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

The NM_000834.5(GRIN2B):c.4197T>C(p.His1399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,904 control chromosomes in the GnomAD database, including 12,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 3007 hom., cov: 33)

Exomes 𝑓: 0.10 ( 9505 hom. )

Consequence

GRIN2B
NM_000834.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.0850

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=-0.56).

BP6

Variant 12-13563041-A-G is Benign according to our data. Variant chr12-13563041-A-G is described in ClinVar as [Benign]. Clinvar id is 98432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13563041-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.085 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRIN2B	NM_000834.5 linkuse as main transcript	c.4197T>C	p.His1399=	synonymous_variant	14/14	ENST00000609686.4	NP_000825.2
GRIN2B	NM_001413992.1 linkuse as main transcript	c.4197T>C	p.His1399=	synonymous_variant	15/15		NP_001400921.1
GRIN2B	XM_005253351.3 linkuse as main transcript	c.1983T>C	p.His661=	synonymous_variant	4/4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4 linkuse as main transcript	c.4197T>C	p.His1399=	synonymous_variant	14/14	1	NM_000834.5	ENSP00000477455	P1
GRIN2B	ENST00000637214.1 linkuse as main transcript	c.69+45562T>C		intron_variant		5		ENSP00000489997

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25199

AN:

152054

Hom.:

2982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.333

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.0845

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0845

Gnomad OTH

AF:

0.154

GnomAD3 exomes

AF:

0.130

AC:

32584

AN:

251330

Hom.:

2779

AF XY:

0.129

AC XY:

17501

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.334

Gnomad AMR exome

AF:

0.117

Gnomad ASJ exome

AF:

0.0872

Gnomad EAS exome

AF:

0.168

Gnomad SAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.107

Gnomad NFE exome

AF:

0.0868

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0999

AC:

146040

AN:

1461732

Hom.:

9505

Cov.:

AF XY:

0.103

AC XY:

74824

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.343

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.0867

Gnomad4 EAS exome

AF:

0.204

Gnomad4 SAS exome

AF:

0.204

Gnomad4 FIN exome

AF:

0.111

Gnomad4 NFE exome

AF:

0.0790

Gnomad4 OTH exome

AF:

0.114

GnomAD4 genome

AF:

0.166

AC:

25263

AN:

152172

Hom.:

3007

Cov.:

AF XY:

0.166

AC XY:

12353

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.333

Gnomad4 AMR

AF:

0.120

Gnomad4 ASJ

AF:

0.0845

Gnomad4 EAS

AF:

0.182

Gnomad4 SAS

AF:

0.214

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.0845

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.104

Hom.:

1584

Bravo

AF:

0.173

Asia WGS

AF:

0.199

AC:

693

AN:

3478

EpiCase

AF:

0.0846

EpiControl

AF:

0.0799

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
not provided, no classification provided	literature only	Psychiatry Genetics Yale University	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:2

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, 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 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

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

- -

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

-0.56

CADD

Benign

2.2

DANN

Benign

0.51

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