16-9834227-G-C

Position:

• chr16-9834227-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001134407.3(GRIN2A):​c.1655C>G​(p.Pro552Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.71

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a mutagenesis_site Changed glutamate-gated calcium ion channel activity characterized by accelerated response activation time and increased desensitization. (size 0) in uniprot entity NMDE1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.945
• PP5: Variant 16-9834227-G-C is Pathogenic according to our data. Variant chr16-9834227-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 39663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-9834227-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.1655C>G	p.Pro552Arg	missense_variant	8/13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.1655C>G	p.Pro552Arg	missense_variant	8/13	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Landau-Kleffner syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 06, 2020	Criteria applied: PS2,PS3_MOD,PS4_MOD,PM2_SUP,PM5_SUP,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 18, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2024

The c.1655C>G (p.P552R) alteration is located in exon 9 (coding exon 7) of the GRIN2A gene. This alteration results from a C to G substitution at nucleotide position 1655, causing the proline (P) at amino acid position 552 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals with profound to severe intellectual disability, seizures, spasticity, and other clinical features consistent with GRIN2A-related speech disorders and epilepsy (de Ligt, 2012; Strehlow, 2019). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In multiple assays testing GRIN2A function, this variant showed functionally abnormal results (Ogden, 2017; Gale, 2021; Iacobucci, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.0	M;.;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.2	D;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MutPred		0.77		Gain of solvent accessibility (P = 0.0584);.;Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP		0.89
MPC		2.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.90
gMVP		1.0

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: rs397518450; hg19: chr16-9928084;