rs75761674

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001134407.3(GRIN2A):c.3578T>G(p.Leu1193Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000793 in 1,614,110 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).

Frequency

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

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 4.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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=0.20921835).

BP6

Variant 16-9763966-A-C is Benign according to our data. Variant chr16-9763966-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205675.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000821 (120/1461872) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 65 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3 linkuse as main transcript	c.3578T>G	p.Leu1193Trp	missense_variant	13/13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4 linkuse as main transcript	c.3578T>G	p.Leu1193Trp	missense_variant	13/13	1	NM_001134407.3	ENSP00000332549	P1	Q12879-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152120

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251344

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Landau-Kleffner syndrome

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	GRIN2A: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 28, 2015

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

This 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

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.50

D;.;.;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.;M;M

MutationTaster

Benign

0.91

D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.73

N;.;N;N

REVEL

Benign

0.22

Sift

Benign

0.074

T;.;T;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.99

D;.;.;D

Vest4

0.30

MutPred

0.62

Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.29

MPC

1.1

ClinPred

0.14

GERP RS

3.0

Varity_R

0.056

gMVP

0.36

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