16-9763418-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001134407.3(GRIN2A):c.4126C>A(p.Arg1376Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. 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. R1376C) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRIN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.23374206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.4126C>A	p.Arg1376Ser	missense_variant	13/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.4126C>A	p.Arg1376Ser	missense_variant	13/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Landau-Kleffner syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1376 of the GRIN2A protein (p.Arg1376Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 28109652). ClinVar contains an entry for this variant (Variation ID: 1373830). 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 not expected to disrupt GRIN2A protein function. 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. -

Complex neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 24, 2023

The GRIN2A c.4126C>A (p.Arg1376Ser) missense variant results in the substitution of arginine at amino acid position 1376 with serine. This variant has been reported in one individual with onset of febrile seizures at 18 months, who inherited the variant from their unaffected father (PMID: 28109652). Another missense variant at the same residue, c.4126C>T (p.Arg1376Cys), was reported in a proband with seizure onset at 28 months. The variant did not segregate with the disorder in the family (PMID: 33240831). The c.4126C>A variant is reported in one allele at a frequency of 0.000015 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.4126C>A (p.Arg1376Ser) variant is classified as a variant of uncertain significance for complex neurodevelopmental disorder. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	0.039
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D;N;N;N
REVEL	Benign	0.13
Sift4G	Benign	0.35	T;T
Vest4		0.22
MVP		0.22
ClinPred		0.88	D
GERP RS		5.6

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: rs1426934537; hg19: chr16-9857275; COSMIC: COSV58024387; COSMIC: COSV58024387;