NM_001134407.3:c.4205G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001134407.3(GRIN2A):​c.4205G>T​(p.Arg1402Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1402P) has been classified as Likely benign.

Frequency

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

Consequence

GRIN2A
NM_001134407.3 missense

Scores

8
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.67

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • complex neurodevelopmental disorder
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • Landau-Kleffner syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • continuous spikes and waves during sleep
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • rolandic epilepsy-speech dyspraxia syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • self-limited epilepsy with centrotemporal spikes
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • neurodevelopmental disorder
    Inheritance: AR Classification: LIMITED Submitted by: G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRIN2ANM_001134407.3 linkc.4205G>T p.Arg1402Leu missense_variant Exon 13 of 13 ENST00000330684.4 NP_001127879.1 Q12879-1Q547U9Q59EW6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRIN2AENST00000330684.4 linkc.4205G>T p.Arg1402Leu missense_variant Exon 13 of 13 1 NM_001134407.3 ENSP00000332549.3 Q12879-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461860
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111986
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.010
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D;D
Eigen
Benign
0.056
Eigen_PC
Benign
0.085
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.90
.;D
M_CAP
Benign
0.067
D
MetaRNN
Uncertain
0.64
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
M;M
PhyloP100
4.7
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.19
Sift
Uncertain
0.0030
D;D
Sift4G
Benign
0.089
T;T
Polyphen
0.72
P;P
Vest4
0.65
MutPred
0.62
Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);
MVP
0.43
MPC
0.53
ClinPred
0.93
D
GERP RS
3.9
Varity_R
0.22
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

Other links and lift over

dbSNP: rs74935155; hg19: chr16-9857196; COSMIC: COSV100411016; COSMIC: COSV100411016; API