rs1805247

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000834.5(GRIN2B):c.4197T>C(p.His1399His) 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

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
developmental and epileptic encephalopathy, 27
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
intellectual disability, autosomal dominant 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GRIN2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 98432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5 link	c.4197T>C	p.His1399His	synonymous_variant	Exon 14 of 14	ENST00000609686.4	NP_000825.2	Q13224A0A8D9PHB2
GRIN2B	NM_001413992.1 link	c.4197T>C	p.His1399His	synonymous_variant	Exon 15 of 15		NP_001400921.1
GRIN2B	XM_005253351.3 link	c.1983T>C	p.His661His	synonymous_variant	Exon 4 of 4		XP_005253408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4 link	c.4197T>C	p.His1399His	synonymous_variant	Exon 14 of 14	1	NM_000834.5	ENSP00000477455.1		Q13224

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

GnomAD2 exomes

AF:

0.130

AC:

32584

AN:

251330

AF XY:

0.129

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 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

African (AFR)

AF:

0.343

AC:

11494

AN:

33476

American (AMR)

AF:

0.117

AC:

5210

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0867

AC:

2265

AN:

26134

East Asian (EAS)

AF:

0.204

AC:

8112

AN:

39694

South Asian (SAS)

AF:

0.204

AC:

17616

AN:

86252

European-Finnish (FIN)

AF:

0.111

AC:

5908

AN:

53392

Middle Eastern (MID)

AF:

0.120

AC:

694

AN:

5768

European-Non Finnish (NFE)

AF:

0.0790

AC:

87872

AN:

1111910

Other (OTH)

AF:

0.114

AC:

6869

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

8210

16420

24630

32840

41050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3422

6844

10266

13688

17110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.166

AC:

25263

AN:

152172

Hom.:

3007

Cov.:

AF XY:

0.166

AC XY:

12353

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.333

AC:

13835

AN:

41500

American (AMR)

AF:

0.120

AC:

1839

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0845

AC:

293

AN:

3466

East Asian (EAS)

AF:

0.182

AC:

936

AN:

5154

South Asian (SAS)

AF:

0.214

AC:

1029

AN:

4814

European-Finnish (FIN)

AF:

0.106

AC:

1120

AN:

10616

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0845

AC:

5747

AN:

68006

Other (OTH)

AF:

0.152

AC:

320

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1003

2006

3009

4012

5015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.113

Hom.:

2587

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

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Psychiatry Genetics Yale University

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 6

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 27

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.2

(source)

DANN

Benign

0.51

PhyloP100

-0.085

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over