16-9764316-G-T

Position:

chr16-9764316-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001134407.3(GRIN2A):c.3228C>A(p.Asn1076Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,614,114 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin Lovd.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 29 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.40

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:

GRIN2A (HGNC:):

GRIN2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=0.0055758953).

BP6

Variant 16-9764316-G-T is Benign according to our data. Variant chr16-9764316-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 129196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-9764316-G-T is described in Lovd as [Likely_benign]. Variant chr16-9764316-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00447 (681/152250) while in subpopulation AMR AF= 0.00831 (127/15290). AF 95% confidence interval is 0.00713. There are 3 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 681 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3 linkuse as main transcript	c.3228C>A	p.Asn1076Lys	missense_variant	13/13	ENST00000330684.4	NP_001127879.1	Q12879-1Q547U9Q59EW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4 linkuse as main transcript	c.3228C>A	p.Asn1076Lys	missense_variant	13/13	1	NM_001134407.3	ENSP00000332549.3		Q12879-1

Frequencies

GnomAD3 genomes

AF:

0.00447

AC:

680

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00832

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00650

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00421

AC:

1059

AN:

251398

Hom.:

AF XY:

0.00423

AC XY:

575

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000915

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00690

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00567

AC:

8288

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3965

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00257

Gnomad4 ASJ exome

AF:

0.00513

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.00268

Gnomad4 NFE exome

AF:

0.00673

Gnomad4 OTH exome

AF:

0.00483

GnomAD4 genome

AF:

0.00447

AC:

681

AN:

152250

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

346

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.00831

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.00650

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00599

Hom.:

Bravo

AF:

0.00479

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00435

AC:

528

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2014	The variant is found in CHILD-EPI,EPILEPSY,INFANT-EPI panel(s). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GRIN2A: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Landau-Kleffner syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 18, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.8% (127/15270) including at least 1 homozygote (https://gnomad.broadinstitute.org/variant/16-9764316-G-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign/Likely Benign (Variation ID:129196). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2018

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

0.24

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

.;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0056

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;M;M

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.0

N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.14

T;.;T;T

Sift4G

Uncertain

0.039

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.52

MutPred

0.46

Gain of MoRF binding (P = 0.0255);.;Gain of MoRF binding (P = 0.0255);Gain of MoRF binding (P = 0.0255);

MVP

0.71

MPC

0.72

ClinPred

0.014

GERP RS

4.5

Varity_R

0.12

gMVP

0.20

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