16-9938419-A-T

Position:

chr16-9938419-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PP2PP3_ModerateBP6BS1BS2

The NM_001134407.3(GRIN2A):c.547T>A(p.Phe183Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:5

Conservation

PhyloP100: 9.21

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 Likely_benign. Variant got -6 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). The gene has 92 curated pathogenic missense variants (we use a threshold of 10). The gene has 175 curated benign missense variants. GenCC has associacion of the 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

BP6

Variant 16-9938419-A-T is Benign according to our data. Variant chr16-9938419-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129189.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=3, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000198 (290/1461528) while in subpopulation NFE AF= 0.000254 (282/1111710). AF 95% confidence interval is 0.000229. There are 0 homozygotes in gnomad4_exome. There are 141 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3 link	c.547T>A	p.Phe183Ile	missense_variant	3/13	ENST00000330684.4	NP_001127879.1	Q12879-1Q547U9Q59EW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4 link	c.547T>A	p.Phe183Ile	missense_variant	3/13	1	NM_001134407.3	ENSP00000332549.3		Q12879-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152144

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250794

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135540

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000198

AC:

290

AN:

1461528

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727078

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74318

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 10, 2023	PP3, PP4, PM2_SUP -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2017	- -

Landau-Kleffner syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 04, 2024	Variant summary: GRIN2A c.547T>A (p.Phe183Ile) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250794 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GRIN2A causing Epilepsy, Focal, With Speech Disorder And With Or Without Mental Retardation, allowing no conclusion about variant significance. c.547T>A has been reported in the literature in individuals affected with clinical features of GRIN2A-related conditions (example, Bobboli_2018, Lemke_2013). These report(s) do not provide unequivocal conclusions about association of the variant with GRIN2A-related conditions. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (example, Serraz_2016). The following publications have been ascertained in the context of this evaluation (PMID: 29358611, 23933819, 27288002). ClinVar contains an entry for this variant (Variation ID: 129189). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2013	- -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2017

The p.F183I variant (also known as c.547T>A), located in coding exon 2 of the GRIN2A gene, results from a T to A substitution at nucleotide position 547. The phenylalanine at codon 183 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this variant was detected in an individual with benign epilepsy with centrotemporal spikes (rolandic epilepsy). The variant was not present in the patient's asymptomatic father (mother's variant status unknown) (Lemke JR et al. Nat. Genet., 2013 Sep;45:1067-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

GRIN2A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.80

D;.;.;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

.;D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.85

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.6

M;.;M;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.4

D;.;D;D;.

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;.

Polyphen

1.0

D;.;.;D;.

Vest4

0.89

MutPred

0.31

Loss of ubiquitination at K188 (P = 0.1037);.;Loss of ubiquitination at K188 (P = 0.1037);Loss of ubiquitination at K188 (P = 0.1037);.;

MVP

0.93

MPC

1.9

ClinPred

0.61

GERP RS

5.5

Varity_R

0.92

gMVP

0.94

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