16-9938544-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_001134407.3(GRIN2A):​c.422C>A​(p.Thr141Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,603,090 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T141M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

2
17

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.87
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 -13 ACMG points.

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=0.07207945).
BP6
Variant 16-9938544-G-T is Benign according to our data. Variant chr16-9938544-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 590147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GRIN2ANM_001134407.3 linkuse as main transcriptc.422C>A p.Thr141Lys missense_variant 3/13 ENST00000330684.4 NP_001127879.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GRIN2AENST00000330684.4 linkuse as main transcriptc.422C>A p.Thr141Lys missense_variant 3/131 NM_001134407.3 ENSP00000332549 P1Q12879-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000809
AC:
19
AN:
235002
Hom.:
0
AF XY:
0.0000699
AC XY:
9
AN XY:
128780
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000656
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000130
Gnomad OTH exome
AF:
0.000335
GnomAD4 exome
AF:
0.0000414
AC:
60
AN:
1450774
Hom.:
0
Cov.:
31
AF XY:
0.0000415
AC XY:
30
AN XY:
722128
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000464
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152316
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000136
Hom.:
3
Bravo
AF:
0.0000151
ExAC
AF:
0.000149
AC:
18

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Landau-Kleffner syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 07, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 22, 2018This 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. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024GRIN2A: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
14
DANN
Benign
0.84
DEOGEN2
Benign
0.18
T;.;.;T;.
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.54
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.78
.;T;T;T;T
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.072
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.69
N;.;N;N;.
MutationTaster
Benign
1.0
D;N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
0.40
N;.;N;N;.
REVEL
Benign
0.19
Sift
Benign
0.55
T;.;T;T;.
Sift4G
Benign
1.0
T;T;T;T;.
Polyphen
0.0010
B;.;.;B;.
Vest4
0.37
MutPred
0.51
Gain of ubiquitination at T141 (P = 0.0146);.;Gain of ubiquitination at T141 (P = 0.0146);Gain of ubiquitination at T141 (P = 0.0146);.;
MVP
0.60
MPC
0.74
ClinPred
0.015
T
GERP RS
1.6
Varity_R
0.052
gMVP
0.76

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: rs78631453; hg19: chr16-10032401; API