rs1555488144

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

8
10
1

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]

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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 gene, where missense usually causes diseases (based on misZ statistic), GRIN2A. . Gene score misZ 2.8278 (greater than the threshold 3.09). Trascript score misZ 3.7088 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons MANE Protein UniProt
GRIN2ANM_001134407.3 linkuse as main transcriptc.2179G>A p.Ala727Thr missense_variant 11/13 ENST00000330684.4 NP_001127879.1 Q12879-1Q547U9Q59EW6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GRIN2AENST00000330684.4 linkuse as main transcriptc.2179G>A p.Ala727Thr missense_variant 11/131 NM_001134407.3 ENSP00000332549.3 Q12879-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461650
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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.:
32

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
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 05, 2023This 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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 433124). 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. Experimental studies have shown that this missense change affects GRIN2A function (PMID: 27839871). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedresearchGene Discovery Core-Manton Center, Boston Children's HospitalFeb 14, 2020This 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) -
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 14, 2023Identified 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) -
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2018- -
Childhood epilepsy with centrotemporal spikes Pathogenic:1
Pathogenic, no assertion criteria providedcase-controlBioinformatics Core, Luxembourg Center for Systems BiomedicineJan 01, 2017CAADphred>15 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;.;.;D
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
.;D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
-0.034
T
MutationAssessor
Pathogenic
2.9
M;.;M;M
PrimateAI
Pathogenic
0.90
D
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
D
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.

Other links and lift over

dbSNP: rs1555488144; hg19: chr16-9892311; COSMIC: COSV58051418; API