chr16-9938304-T-C

Position:

chr16-9938304-T-C

Variant summary

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

The NM_001134407.3(GRIN2A):c.662A>G(p.Lys221Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000504 in 1,614,048 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K221N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

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 -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=0.009244144).

BP6

Variant 16-9938304-T-C is Benign according to our data. Variant chr16-9938304-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-9938304-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00298 (454/152330) while in subpopulation AFR AF= 0.0106 (440/41570). AF 95% confidence interval is 0.00977. There are 1 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3 linkuse as main transcript	c.662A>G	p.Lys221Arg	missense_variant	3/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4 linkuse as main transcript	c.662A>G	p.Lys221Arg	missense_variant	3/13	1	NM_001134407.3	P1	Q12879-1

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

454

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000653

AC:

164

AN:

251060

Hom.:

AF XY:

0.000494

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.00947

Gnomad AMR exome

AF:

0.000260

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000246

AC:

360

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00929

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.00298

AC:

454

AN:

152330

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

216

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0106

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000546

Hom.:

Bravo

AF:

0.00309

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Landau-Kleffner syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -

not provided

Benign:2

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	Aug 01, 2024	GRIN2A: BS1 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 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

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;.;T;.

Eigen

Benign

-0.088

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

.;D;D;D;D

MetaRNN

Benign

0.0092

T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.0

L;.;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

N;.;N;N;.

REVEL

Benign

0.27

Sift

Benign

0.32

T;.;T;T;.

Sift4G

Benign

0.35

T;T;T;T;.

Polyphen

0.045

B;.;.;B;.

Vest4

0.33

MVP

0.82

MPC

0.52

ClinPred

0.019

GERP RS

5.1

Varity_R

0.20

gMVP

0.40

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