chr16-9764068-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001134407.3(GRIN2A):c.3476G>A(p.Arg1159His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1159C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.08

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Landau-Kleffner syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
continuous spikes and waves during sleep
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
rolandic epilepsy-speech dyspraxia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

GRIN2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06442469).

BP6

Variant 16-9764068-C-T is Benign according to our data. Variant chr16-9764068-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422401.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134407.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2A	NM_001134407.3	MANE Select	c.3476G>A	p.Arg1159His	missense	Exon 13 of 13	NP_001127879.1	Q12879-1
GRIN2A	NM_000833.5		c.3476G>A	p.Arg1159His	missense	Exon 14 of 14	NP_000824.1	Q12879-1
GRIN2A	NM_001134408.2		c.3476G>A	p.Arg1159His	missense	Exon 13 of 14	NP_001127880.1	Q12879-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.3476G>A	p.Arg1159His	missense	Exon 13 of 13	ENSP00000332549.3	Q12879-1
GRIN2A	ENST00000396573.6	TSL:1	c.3476G>A	p.Arg1159His	missense	Exon 14 of 14	ENSP00000379818.2	Q12879-1
GRIN2A	ENST00000562109.5	TSL:1	c.3476G>A	p.Arg1159His	missense	Exon 13 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

251164

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461440

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000134

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111610

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41532

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Landau-Kleffner syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.37

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.84

PhyloP100

3.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.54

REVEL

Benign

0.046

Sift

Benign

0.16

Sift4G

Benign

0.16

Polyphen

0.0080

Vest4

0.089

MutPred

0.54

Loss of stability (P = 0.0211)

MVP

0.40

MPC

0.31

ClinPred

0.025

GERP RS

1.7

Varity_R

0.032

gMVP

0.39

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over