rs1805246

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000834.5(GRIN2B):c.4218C>T(p.Phe1406Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0367 in 1,613,930 control chromosomes in the GnomAD database, including 1,338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 98 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1240 hom. )

Consequence

GRIN2B
NM_000834.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.20

Publications

10 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 12-13563020-G-A is Benign according to our data. Variant chr12-13563020-G-A is described in ClinVar as Benign. ClinVar VariationId is 98431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5 link	c.4218C>T	p.Phe1406Phe	synonymous_variant	Exon 14 of 14	ENST00000609686.4	NP_000825.2	Q13224A0A8D9PHB2
GRIN2B	NM_001413992.1 link	c.4218C>T	p.Phe1406Phe	synonymous_variant	Exon 15 of 15		NP_001400921.1
GRIN2B	XM_005253351.3 link	c.2004C>T	p.Phe668Phe	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.4218C>T	p.Phe1406Phe	synonymous_variant	Exon 14 of 14	1	NM_000834.5	ENSP00000477455.1		Q13224

Frequencies

GnomAD3 genomes

AF:

0.0284

AC:

4328

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00697

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.0861

Gnomad SAS

AF:

0.0760

Gnomad FIN

AF:

0.0115

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0400

Gnomad OTH

AF:

0.0235

GnomAD2 exomes

AF:

0.0367

AC:

9228

AN:

251330

AF XY:

0.0389

show subpopulations

Gnomad AFR exome

AF:

0.00635

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.0874

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0364

Gnomad OTH exome

AF:

0.0341

GnomAD4 exome

AF:

0.0376

AC:

54901

AN:

1461600

Hom.:

1240

Cov.:

AF XY:

0.0387

AC XY:

28108

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.00603

AC:

202

AN:

33478

American (AMR)

AF:

0.0165

AC:

740

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0220

AC:

576

AN:

26134

East Asian (EAS)

AF:

0.0704

AC:

2793

AN:

39690

South Asian (SAS)

AF:

0.0689

AC:

5940

AN:

86256

European-Finnish (FIN)

AF:

0.0149

AC:

793

AN:

53386

Middle Eastern (MID)

AF:

0.0359

AC:

207

AN:

5768

European-Non Finnish (NFE)

AF:

0.0371

AC:

41269

AN:

1111780

Other (OTH)

AF:

0.0394

AC:

2381

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

3340

6680

10021

13361

16701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1580

3160

4740

6320

7900

<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:

0.0284

AC:

4326

AN:

152330

Hom.:

Cov.:

AF XY:

0.0280

AC XY:

2085

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00695

AC:

289

AN:

41582

American (AMR)

AF:

0.0163

AC:

249

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3468

East Asian (EAS)

AF:

0.0865

AC:

447

AN:

5170

South Asian (SAS)

AF:

0.0759

AC:

366

AN:

4822

European-Finnish (FIN)

AF:

0.0115

AC:

122

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0400

AC:

2719

AN:

68042

Other (OTH)

AF:

0.0232

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

219

438

658

877

1096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0332

Hom.:

Bravo

AF:

0.0258

Asia WGS

AF:

0.0720

AC:

249

AN:

3478

EpiCase

AF:

0.0356

EpiControl

AF:

0.0333

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 26, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Psychiatry Genetics Yale University

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Inborn genetic diseases

Benign:1

Mar 14, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

4.2

Mutation Taster

=96/4

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