16-9822337-G-C

Variant names:

• chr16-9822337-G-C
• NM_001134407.3:c.2095C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001134407.3(GRIN2A):​c.2095C>G​(p.Pro699Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P699S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Extracellular (size 170) in uniprot entity NMDE1_HUMAN there are 45 pathogenic changes around while only 1 benign (98%) 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 chr16-9822337-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the GRIN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 92 curated pathogenic missense variants (we use a threshold of 10). The gene has 175 curated benign missense variants. Gene score misZ: 2.8278 (below the threshold of 3.09). Trascript score misZ: 3.7088 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.2095C>G	p.Pro699Ala	missense_variant	Exon 10 of 13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2095C>G	p.Pro699Ala	missense_variant	Exon 10 of 13	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Uncertain:1

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Pro699Ser amino acid residue in GRIN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23933819, 27839871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GRIN2A protein function. This missense change has been observed in at least one individual who was not affected with GRIN2A-related conditions (Invitae). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 699 of the GRIN2A protein (p.Pro699Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	.;T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L;.;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.26	T;.;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.46
MutPred		0.49		Loss of stability (P = 0.0654);.;Loss of stability (P = 0.0654);Loss of stability (P = 0.0654);
MVP		0.69
MPC		2.5
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-9916194;