rs1448253

Variant names:

• chr16-10127009-C-T
• rs1448253
• NM_001134407.3:c.414+52989G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134407.3(GRIN2A):​c.414+52989G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 152,154 control chromosomes in the GnomAD database, including 55,368 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.85 (55368 hom., cov: 32)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Landau-Kleffner syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• continuous spikes and waves during sleep

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• rolandic epilepsy-speech dyspraxia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• self-limited epilepsy with centrotemporal spikes

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.414+52989G>A		intron_variant	Intron 2 of 12	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.414+52989G>A		intron_variant	Intron 2 of 12	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128837 AN: 152036 Hom.: 55336 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.923

Gnomad ASJ AF: 0.968

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.987

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.887

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.847 AC: 128924 AN: 152154 Hom.: 55368 Cov.: 32 AF XY: 0.852 AC XY: 63375 AN XY: 74372

African (AFR) AF: 0.696 AC: 28887 AN: 41482

American (AMR) AF: 0.923 AC: 14111 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 3362 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5171 AN: 5172

South Asian (SAS) AF: 0.987 AC: 4761 AN: 4822

European-Finnish (FIN) AF: 0.874 AC: 9250 AN: 10580

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.887 AC: 60328 AN: 68020

Other (OTH) AF: 0.887 AC: 1876 AN: 2114

Alfa AF: 0.885 Hom.: 110261

Bravo AF: 0.844

Asia WGS AF: 0.976 AC: 3393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.15
DANN	Benign	0.48
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1448253; hg19: chr16-10220866;