rs775911833

chr16-9763285-T-Achr16-9763285-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_001134407.3(GRIN2A):c.4259A>T(p.Asn1420Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 152,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1420S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000033 (0 hom., cov: 32)
• Consequence: GRIN2A NM_001134407.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 -3 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=0.1842125).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.4259A>T	p.Asn1420Ile	missense_variant	13/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.4259A>T	p.Asn1420Ile	missense_variant	13/13	1	NM_001134407.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152142 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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.95	D;D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.071
Sift	Benign	0.20	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.32	B;B
Vest4		0.19
MutPred		0.53		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.41
MPC		0.51
ClinPred		0.22	T
GERP RS		-1.7
Varity_R		0.12
gMVP		0.22

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: rs775911833; hg19: chr16-9857142;