rs1445802934

chr16-9822363-G-Achr16-9822363-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001134407.3(GRIN2A):c.2069C>T(p.Thr690Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T690K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 9.88

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr16-9822363-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GRIN2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 16-9822363-G-A is Pathogenic according to our data. Variant chr16-9822363-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444362.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.2069C>T	p.Thr690Met	missense_variant	10/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2069C>T	p.Thr690Met	missense_variant	10/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251308 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460102 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Landau-Kleffner syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GRIN2A related disorder (ClinVar ID: VCV000444362 / PMID: 31780880). The variant has been previously reported as de novo in a similarly affected individual (PMID: 31780880). A different missense change at the same codon (p.Thr690Lys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000981282). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2023	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt GRIN2A protein function. ClinVar contains an entry for this variant (Variation ID: 444362). This missense change has been observed in individual(s) with epilepsy (PMID: 31780880). In at least one individual the variant was observed to be de novo. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 690 of the GRIN2A protein (p.Thr690Met). -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Apr 01, 2021

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2014

The c.2069C>T (p.T690M) alteration is located in exon 11 (coding exon 9) of the GRIN2A gene. This alteration results from a C to T substitution at nucleotide position 2069, causing the threonine (T) at amino acid position 690 to be replaced by a methionine (M). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the GRIN2A c.2069C>T alteration was not observed among 6,472 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP)._x000D_ Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered nucleotide is conserved throughout evolution:_x000D_ The c.2069C nucleotide is conserved throughout vertebrates._x000D_ The altered amino acid is conserved throughout evolution:_x000D_ The p.T690 amino acid is conserved throughout vertebrates. The alteration is predicted deleterious by in silico models:_x000D_ The p.T690M alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses._x000D_ The alteration is predicted not to affect splicing by in silico models:_x000D_ Based on BDGP and ESEfinder splice site in silico tools, this alteration does not have any significant effect on the native acceptor/donor splice site; however, direct evidence is unavailable Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	2.9	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D;.;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.90
MutPred		0.52		Loss of phosphorylation at T690 (P = 0.027);.;Loss of phosphorylation at T690 (P = 0.027);Loss of phosphorylation at T690 (P = 0.027);
MVP		0.85
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.94

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: rs1445802934; hg19: chr16-9916220; COSMIC: COSV58023767;