rs1555488144

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001134407.3(GRIN2A):c.2179G>A(p.Ala727Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.77

Variant links:

Genes affected

GRIN2A (HGNC:4585): (glutamate ionotropic receptor NMDA type subunit 2A) This gene encodes a member of the glutamate-gated ion channel protein family. The encoded protein is an N-methyl-D-aspartate (NMDA) receptor subunit. NMDA receptors are both ligand-gated and voltage-dependent, and are involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. These receptors are permeable to calcium ions, and activation results in a calcium influx into post-synaptic cells, which results in the activation of several signaling cascades. Disruption of this gene is associated with focal epilepsy and speech disorder with or without cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

GRIN2A links:

ENSG00000283221 (HGNC:):

ENSG00000283221 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a topological_domain Extracellular (size 170) in uniprot entity NMDE1_HUMAN there are 45 pathogenic changes around while only 1 benign (98%) in NM_001134407.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GRIN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 92 curated pathogenic missense variants (we use a threshold of 10). The gene has 175 curated benign missense variants. Gene score misZ: 2.8278 (below the threshold of 3.09). Trascript score misZ: 3.7088 (above the threshold of 3.09). GenCC associations: The gene is linked to early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation, Landau-Kleffner syndrome, continuous spikes and waves during sleep, complex neurodevelopmental disorder, rolandic epilepsy-speech dyspraxia syndrome, childhood epilepsy with centrotemporal spikes.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 16-9798454-C-T is Pathogenic according to our data. Variant chr16-9798454-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3 link	c.2179G>A	p.Ala727Thr	missense_variant	Exon 11 of 13	ENST00000330684.4	NP_001127879.1	Q12879-1Q547U9Q59EW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4 link	c.2179G>A	p.Ala727Thr	missense_variant	Exon 11 of 13	1	NM_001134407.3	ENSP00000332549.3		Q12879-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727136

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:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Landau-Kleffner syndrome

Pathogenic:3

Feb 14, 2020

Gene Discovery Core-Manton Center, Boston Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant is interpreted as Pathogenic for epilepsy and episodic atazia; Autosomal Dominant. PS2-De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. PS3- Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product, PMID:27839871. PM1- Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM2- Absent from controls in gnomad.PP3- Multiple lines of computational evidence support a deleterious effect on the gene or gene product. (conservation, evolutionary, splicing impact, etc.). PP5- Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation (PMID: 23933819, PMID: 28109652) -

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects GRIN2A function (PMID: 27839871). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GRIN2A protein function. ClinVar contains an entry for this variant (Variation ID: 433124). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 23933819, 28109652; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 727 of the GRIN2A protein (p.Ala727Thr). For these reasons, this variant has been classified as Pathogenic. -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

May 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with epilepsy in the published literature with either unknown segregation or inheritance from an unaffected parent (Lemke et al., 2013; von Stulpnagel et al., 2017); Published functional studies demonstrate reduced glutamate potency compared to wild type (Swanger et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23933819, 29358611, 28109652, 35936491, 36516565, 27839871) -

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Uncertain

-0.034

MutationAssessor

Pathogenic

2.9

M;.;M;M

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.6

D;.;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

0.99

D;.;.;D

Vest4

0.98

MutPred

0.83

Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.86

MPC

2.6

ClinPred

0.99

GERP RS

4.2

Varity_R

0.91

gMVP

0.94

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