Genetic Variant GRIN2B:p.Ala5Ala (chr12-13866194-C-T) – ACMG Classification: Benign (-21 pts)

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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely 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

Publications

17 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=-0.53).

BP6

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIN2B	NM_000834.5	MANE Select	c.15G>A	p.Ala5Ala	synonymous	Exon 3 of 14	NP_000825.2
GRIN2B	NM_001413992.1		c.15G>A	p.Ala5Ala	synonymous	Exon 4 of 15	NP_001400921.1
GRIN2B	NM_001413993.1		c.15G>A	p.Ala5Ala	synonymous	Exon 3 of 4	NP_001400922.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIN2B	ENST00000609686.4	TSL:1 MANE Select	c.15G>A	p.Ala5Ala	synonymous	Exon 3 of 14	ENSP00000477455.1
GRIN2B	ENST00000630791.3	TSL:5	c.15G>A	p.Ala5Ala	synonymous	Exon 4 of 15	ENSP00000486677.3
GRIN2B	ENST00000627535.2	TSL:5	c.15G>A	p.Ala5Ala	synonymous	Exon 3 of 3	ENSP00000486411.1

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

GnomAD2 exomes

AF:

0.0489

AC:

11860

AN:

242460

AF XY:

0.0528

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 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

African (AFR)

AF:

0.00621

AC:

208

AN:

33478

American (AMR)

AF:

0.0110

AC:

494

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26136

East Asian (EAS)

AF:

0.0939

AC:

3722

AN:

39658

South Asian (SAS)

AF:

0.0975

AC:

8410

AN:

86240

European-Finnish (FIN)

AF:

0.0927

AC:

4520

AN:

48756

Middle Eastern (MID)

AF:

0.0121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0359

AC:

39869

AN:

1111846

Other (OTH)

AF:

0.0417

AC:

2516

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3192

6385

9577

12770

15962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1534

3068

4602

6136

7670

<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:

0.0351

AC:

5338

AN:

152206

Hom.:

200

Cov.:

AF XY:

0.0396

AC XY:

2950

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00746

AC:

310

AN:

41554

American (AMR)

AF:

0.0150

AC:

229

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3468

East Asian (EAS)

AF:

0.120

AC:

620

AN:

5146

South Asian (SAS)

AF:

0.101

AC:

485

AN:

4816

European-Finnish (FIN)

AF:

0.0947

AC:

1004

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0384

AC:

2610

AN:

68012

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

248

496

743

991

1239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0317

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

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

Sep 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Oct 25, 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.

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

Mar 24, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.5

(source)

DANN

Benign

0.78

PhyloP100

0.029

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over