NM_000834.5:c.140A>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

The NM_000834.5(GRIN2B):c.140A>G(p.Glu47Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000075 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

GRIN2B
NM_000834.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.11

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in the GRIN2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 118 curated benign missense variants. Gene score misZ: 5.4168 (above the threshold of 3.09). Trascript score misZ: 7.3273 (above the threshold of 3.09). GenCC associations: The gene is linked to autism susceptibility 1, developmental and epileptic encephalopathy, 27, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, West syndrome, intellectual disability, autosomal dominant 6.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

BP6

Variant 12-13866069-T-C is Benign according to our data. Variant chr12-13866069-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205708.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr12-13866069-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5 link	c.140A>G	p.Glu47Gly	missense_variant	Exon 3 of 14	ENST00000609686.4	NP_000825.2	Q13224A0A8D9PHB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRIN2B	ENST00000609686.4 link	c.140A>G	p.Glu47Gly	missense_variant	Exon 3 of 14	1	NM_000834.5	ENSP00000477455.1	Q13224
GRIN2B	ENST00000630791.2 link	c.140A>G	p.Glu47Gly	missense_variant	Exon 4 of 8	5		ENSP00000486677.3	A0A0D9SFK0
GRIN2B	ENST00000627535.2 link	c.*34A>G		downstream_gene_variant		5		ENSP00000486411.1	A0A0D9SFA0

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250734

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 30, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Sep 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27029629, 29124671) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.72

M_CAP

Benign

0.0094

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.74

Sift4G

Uncertain

0.015

Polyphen

0.99

Vest4

0.79

MVP

0.97

MPC

1.7

ClinPred

0.46

GERP RS

5.7

Varity_R

0.68

gMVP

0.96

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