Genetic Variant GRIN2A:p.Arg518His (chr16-9840745-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001134407.3(GRIN2A):c.1553G>A(p.Arg518His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GRIN2A
NM_001134407.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 7.81

Publications

19 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
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: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001134407.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-9840746-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 205687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 16-9840745-C-T is Pathogenic according to our data. Variant chr16-9840745-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 88732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1553G>A	p.Arg518His	missense	Exon 7 of 13	NP_001127879.1	Q12879-1
GRIN2A	NM_000833.5		c.1553G>A	p.Arg518His	missense	Exon 8 of 14	NP_000824.1	Q12879-1
GRIN2A	NM_001134408.2		c.1553G>A	p.Arg518His	missense	Exon 7 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.1553G>A	p.Arg518His	missense	Exon 7 of 13	ENSP00000332549.3	Q12879-1
GRIN2A	ENST00000396573.6	TSL:1	c.1553G>A	p.Arg518His	missense	Exon 8 of 14	ENSP00000379818.2	Q12879-1
GRIN2A	ENST00000562109.5	TSL:1	c.1553G>A	p.Arg518His	missense	Exon 7 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461112

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726860

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111476

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Landau-Kleffner syndrome (4)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

4.0

PhyloP100

7.8

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.94

Loss of sheet (P = 0.0817)

MVP

0.93

MPC

2.9

ClinPred

1.0

GERP RS

5.3

Varity_R

0.93

gMVP

1.0

Mutation Taster

=3/97

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over