rs747214620

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP6BS2

The NM_001134407.3(GRIN2A):c.794C>T(p.Thr265Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.65

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GRIN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 92 curated pathogenic missense variants (we use a threshold of 10). The gene has 175 curated benign missense variants. Gene score misZ: 2.8278 (below the threshold of 3.09). Trascript score misZ: 3.7088 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

BP6

Variant 16-9938172-G-A is Benign according to our data. Variant chr16-9938172-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577489.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3 link	c.794C>T	p.Thr265Met	missense_variant	Exon 3 of 13	ENST00000330684.4	NP_001127879.1	Q12879-1Q547U9Q59EW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4 link	c.794C>T	p.Thr265Met	missense_variant	Exon 3 of 13	1	NM_001134407.3	ENSP00000332549.3		Q12879-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250962

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727178

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Landau-Kleffner syndrome

Uncertain:1Benign:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.794C>Tp.Thr265Met in GRIN2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Thr265Met variant is reported with 0.0004% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Thr at position 265 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence Polyphen-probably damaging, SIFT- Tolerated and Mutation Taster-disease causing predicts conflicting evidence on protein structure and function for this variant. The reference amino acid p.Thr265Met in GRIN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

0.0039

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;.;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

.;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.0

L;.;L;L;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.9

D;.;D;D;.

REVEL

Uncertain

0.46

Sift

Benign

0.12

T;.;T;T;.

Sift4G

Benign

0.20

T;T;T;T;.

Polyphen

1.0

D;.;.;D;.

Vest4

0.62

MutPred

0.44

Loss of catalytic residue at T265 (P = 0.053);.;Loss of catalytic residue at T265 (P = 0.053);Loss of catalytic residue at T265 (P = 0.053);.;

MVP

0.66

MPC

1.4

ClinPred

0.94

GERP RS

5.2

Varity_R

0.22

gMVP

0.60

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over