rs397518466
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_001134407.3(GRIN2A):c.2T>C(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. 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)
Consequence
GRIN2A
NM_001134407.3 start_lost
NM_001134407.3 start_lost
Scores
4
3
8
Clinical Significance
Conservation
PhyloP100: 4.58
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_001134407.3 (GRIN2A) was described as [Likely_pathogenic] in ClinVar as 1685337
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-10180410-A-G is Pathogenic according to our data. Variant chr16-10180410-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-10180410-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRIN2A | NM_001134407.3 | c.2T>C | p.Met1? | start_lost | 2/13 | ENST00000330684.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRIN2A | ENST00000330684.4 | c.2T>C | p.Met1? | start_lost | 2/13 | 1 | NM_001134407.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Landau-Kleffner syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GRIN2A protein in which other variant(s) (p.Leu15Pro) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 88728). Disruption of the initiator codon has been observed in individual(s) with GRIN2A-related conditions (PMID: 23933818). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GRIN2A mRNA. The next in-frame methionine is located at codon 39. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PROVEAN
Benign
N;N;N;.;.
REVEL
Benign
Sift
Pathogenic
D;D;D;.;.
Sift4G
Uncertain
D;D;D;.;.
Polyphen
B;.;B;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at