rs376029542

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 3P and 11B. PM1PP2BP4_ModerateBP6BS1BS2

The NM_001134407.3(GRIN2A):​c.2165C>T​(p.Thr722Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T722T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

2
7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.56
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001134407.3
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.23339662).
BP6
Variant 16-9822267-G-A is Benign according to our data. Variant chr16-9822267-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287546.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00023 (35/152260) while in subpopulation AFR AF= 0.00077 (32/41548). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRIN2ANM_001134407.3 linkuse as main transcriptc.2165C>T p.Thr722Met missense_variant 10/13 ENST00000330684.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRIN2AENST00000330684.4 linkuse as main transcriptc.2165C>T p.Thr722Met missense_variant 10/131 NM_001134407.3 P1Q12879-1

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000797
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000115
AC:
29
AN:
251176
Hom.:
0
AF XY:
0.0000884
AC XY:
12
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.000738
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000424
AC:
62
AN:
1461514
Hom.:
0
Cov.:
31
AF XY:
0.0000385
AC XY:
28
AN XY:
727070
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000230
AC:
35
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.000770
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000322
Hom.:
0
Bravo
AF:
0.000159
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 11, 2016- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 12, 2021This variant is associated with the following publications: (PMID: 28166811, 27839871, 30919572) -
Landau-Kleffner syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeDec 02, 2023- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 05, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.;D
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
.;D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.23
T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.9
L;.;L;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.1
D;.;D;D
REVEL
Benign
0.26
Sift
Benign
0.13
T;.;T;T
Sift4G
Benign
0.15
T;T;T;T
Polyphen
1.0
D;.;.;D
Vest4
0.25
MVP
0.69
MPC
2.5
ClinPred
0.078
T
GERP RS
5.7
Varity_R
0.39
gMVP
0.66

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: rs376029542; hg19: chr16-9916124; COSMIC: COSV58045743; API