rs1555491648

Variant names:

• chr16-9822337-G-A
• rs1555491648
• NM_001134407.3:c.2095C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-9822337-G-A
• chr16-9822337-G-C
• chr16-9822337-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_001134407.3(GRIN2A):​c.2095C>T​(p.Pro699Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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
• 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.
• PP5: Variant 16-9822337-G-A is Pathogenic according to our data. Variant chr16-9822337-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433125.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-9822337-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.2095C>T	p.Pro699Ser	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>T	p.Pro699Ser	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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Pathogenic:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;.;L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D;.;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.10	T;.;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.53
MutPred		0.50		Gain of MoRF binding (P = 0.0522);.;Gain of MoRF binding (P = 0.0522);Gain of MoRF binding (P = 0.0522);
MVP		0.71
MPC		2.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.87

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: rs1555491648; hg19: chr16-9916194; COSMIC: COSV58019167;