rs397518466

Positions:

• chr16-10180410-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001134407.3(GRIN2A):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIN2A NM_001134407.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.58

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-10180410-A-G is Pathogenic according to our data. Variant chr16-10180410-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-10180410-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.2T>C	p.Met1?	start_lost	2/13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2T>C	p.Met1?	start_lost	2/13	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Landau-Kleffner syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GRIN2A protein in which other variant(s) (p.Leu15Pro) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 88728). Disruption of the initiator codon has been observed in individual(s) with GRIN2A-related conditions (PMID: 23933818). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GRIN2A mRNA. The next in-frame methionine is located at codon 39. -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2024

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30544257, 26147798, 27096365, 23933818) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;.;T;.;.
Eigen	Benign	0.061
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D;D;.;.
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.78	N;N;N;.;.
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.018	D;D;D;.;.
Polyphen		0.21	B;.;B;.;.
Vest4		0.75
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);Gain of catalytic residue at M1 (P = 0.0191);
MVP		0.89
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.62

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: rs397518466; hg19: chr16-10274267;