16-9768994-C-T

Position:

• chr16-9768994-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_001134407.3(GRIN2A):​c.2452G>A​(p.Ala818Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A818E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.81

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity NMDE1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr16-9768993-G-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774
• PP5: Variant 16-9768994-C-T is Pathogenic according to our data. Variant chr16-9768994-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522855.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.2452G>A	p.Ala818Thr	missense_variant	12/13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2452G>A	p.Ala818Thr	missense_variant	12/13	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Landau-Kleffner syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2019	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GRIN2A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 818 of the GRIN2A protein (p.Ala818Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jul 31, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M;.;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D;.;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.92
MutPred		0.61		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.78
MPC		0.88
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.69
gMVP		0.91

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

Other links and lift over

dbSNP: rs1555483699; hg19: chr16-9862851; COSMIC: COSV58056466;