rs11866385

Variant names:

• chr16-10014801-C-G
• rs11866385
• NM_001134407.3:c.415-76250G>C

Variant summary

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

The NM_001134407.3(GRIN2A):​c.415-76250G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 151,932 control chromosomes in the GnomAD database, including 8,190 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 0.31 (8190 hom., cov: 32)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134407.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	NM_001134407.3	MANE Select	c.415-76250G>C		intron	N/A	NP_001127879.1
	GRIN2A	NM_000833.5		c.415-76250G>C		intron	N/A	NP_000824.1
	GRIN2A	NM_001134408.2		c.415-76250G>C		intron	N/A	NP_001127880.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.415-76250G>C		intron	N/A	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.415-76250G>C		intron	N/A	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.415-76250G>C		intron	N/A	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46673 AN: 151814 Hom.: 8192 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.332

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

GnomAD4 genome AF: 0.307 AC: 46676 AN: 151932 Hom.: 8190 Cov.: 32 AF XY: 0.305 AC XY: 22623 AN XY: 74230

African (AFR) AF: 0.168 AC: 6946 AN: 41446

American (AMR) AF: 0.339 AC: 5188 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1228 AN: 3468

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5178

South Asian (SAS) AF: 0.219 AC: 1053 AN: 4810

European-Finnish (FIN) AF: 0.421 AC: 4425 AN: 10508

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26445 AN: 67922

Other (OTH) AF: 0.329 AC: 695 AN: 2114

Alfa AF: 0.342 Hom.: 1170

Bravo AF: 0.297

Asia WGS AF: 0.143 AC: 498 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.034
DANN	Benign	0.39
PhyloP100		-2.3
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: rs11866385; hg19: chr16-10108658;