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rs953400144

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001134407.3(GRIN2A):c.886A>G(p.Ile296Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, GRIN2A
BP4
Computational evidence support a benign effect (MetaRNN=0.0705598).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRIN2ANM_001134407.3 linkuse as main transcriptc.886A>G p.Ile296Val missense_variant 3/13 ENST00000330684.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRIN2AENST00000330684.4 linkuse as main transcriptc.886A>G p.Ile296Val missense_variant 3/131 NM_001134407.3 P1Q12879-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461774
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727192
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Landau-Kleffner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 05, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 296 of the GRIN2A protein (p.Ile296Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GRIN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532707). 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 not expected to disrupt GRIN2A protein function. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
Cadd
Benign
14
Dann
Benign
0.30
DEOGEN2
Benign
0.17
T;.;.;T;.
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.77
D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.071
T;T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
-1.1
N;.;N;N;.
MutationTaster
Benign
0.58
N;N;N;N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
0.37
N;.;N;N;.
REVEL
Benign
0.22
Sift
Benign
1.0
T;.;T;T;.
Sift4G
Benign
1.0
T;T;T;T;.
Polyphen
0.0
B;.;.;B;.
Vest4
0.16
MutPred
0.36
Gain of methylation at R293 (P = 0.1168);.;Gain of methylation at R293 (P = 0.1168);Gain of methylation at R293 (P = 0.1168);.;
MVP
0.32
MPC
0.50
ClinPred
0.079
T
GERP RS
4.2
Varity_R
0.056
gMVP
0.48

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: rs953400144; hg19: chr16-10031937; API