rs1060503230

Positions:

• chr16-9768897-G-A
• chr16-9768897-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001134407.3(GRIN2A):​c.2549C>T​(p.Thr850Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T850T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.40189594).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.2549C>T	p.Thr850Met	missense_variant	12/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2549C>T	p.Thr850Met	missense_variant	12/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251024 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 11, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GRIN2A-related disease. This sequence change replaces threonine with methionine at codon 850 of the GRIN2A protein (p.Thr850Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.41	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.45	T;.;T;T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.73
MutPred		0.59		Loss of catalytic residue at T850 (P = 0.126);.;Loss of catalytic residue at T850 (P = 0.126);Loss of catalytic residue at T850 (P = 0.126);
MVP		0.51
MPC		0.91
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.12
gMVP		0.72

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: rs1060503230; hg19: chr16-9862754; COSMIC: COSV58025417;