16-9849809-C-T

Position:

chr16-9849809-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001134407.3(GRIN2A):c.1275G>A(p.Leu425=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,613,150 control chromosomes in the GnomAD database, including 61,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5829 hom., cov: 31)

Exomes 𝑓: 0.27 ( 56057 hom. )

Consequence

GRIN2A
NM_001134407.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.484

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 16-9849809-C-T is Benign according to our data. Variant chr16-9849809-C-T is described in ClinVar as [Benign]. Clinvar id is 129190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-9849809-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.484 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3 linkuse as main transcript	c.1275G>A	p.Leu425=	synonymous_variant	5/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4 linkuse as main transcript	c.1275G>A	p.Leu425=	synonymous_variant	5/13	1	NM_001134407.3	P1	Q12879-1

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41381

AN:

151790

Hom.:

5824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.299

Gnomad AMI

AF:

0.356

Gnomad AMR

AF:

0.235

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.0680

Gnomad SAS

AF:

0.205

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.264

GnomAD3 exomes

AF:

0.249

AC:

62527

AN:

251348

Hom.:

8358

AF XY:

0.250

AC XY:

34025

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.293

Gnomad EAS exome

AF:

0.0665

Gnomad SAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.264

Gnomad NFE exome

AF:

0.285

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.273

AC:

398803

AN:

1461242

Hom.:

56057

Cov.:

AF XY:

0.272

AC XY:

197611

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.302

Gnomad4 AMR exome

AF:

0.206

Gnomad4 ASJ exome

AF:

0.292

Gnomad4 EAS exome

AF:

0.0616

Gnomad4 SAS exome

AF:

0.222

Gnomad4 FIN exome

AF:

0.265

Gnomad4 NFE exome

AF:

0.287

Gnomad4 OTH exome

AF:

0.269

GnomAD4 genome

AF:

0.272

AC:

41392

AN:

151908

Hom.:

5829

Cov.:

AF XY:

0.266

AC XY:

19715

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.299

Gnomad4 AMR

AF:

0.235

Gnomad4 ASJ

AF:

0.290

Gnomad4 EAS

AF:

0.0682

Gnomad4 SAS

AF:

0.203

Gnomad4 FIN

AF:

0.257

Gnomad4 NFE

AF:

0.286

Gnomad4 OTH

AF:

0.263

Alfa

AF:

0.280

Hom.:

9803

Bravo

AF:

0.272

Asia WGS

AF:

0.143

AC:

503

AN:

3476

EpiCase

AF:

0.283

EpiControl

AF:

0.280

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 36. Only high quality variants are reported. -

Landau-Kleffner syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2015

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.3

DANN

Benign

0.80

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