chr16-9793387-A-G

Variant names:

• chr16-9793387-A-G
• rs1544604
• NM_001134407.3:c.2356+4890T>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.2356+4890T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 151,906 control chromosomes in the GnomAD database, including 11,442 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 0.37 (11442 hom., cov: 31)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• Publications: 3 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

LOC105371077 (HGNC:):

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 (AFR) allele frequency at 95% confidence interval = 0.534 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.2356+4890T>C		intron	N/A	NP_001127879.1
	GRIN2A	NM_000833.5		c.2356+4890T>C		intron	N/A	NP_000824.1
	GRIN2A	NM_001134408.2		c.2356+4890T>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.2356+4890T>C		intron	N/A	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.2356+4890T>C		intron	N/A	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.2356+4890T>C		intron	N/A	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56685 AN: 151788 Hom.: 11419 Cov.: 31

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.358

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

GnomAD4 genome AF: 0.374 AC: 56750 AN: 151906 Hom.: 11442 Cov.: 31 AF XY: 0.368 AC XY: 27346 AN XY: 74286

African (AFR) AF: 0.540 AC: 22347 AN: 41386

American (AMR) AF: 0.293 AC: 4465 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3472

East Asian (EAS) AF: 0.260 AC: 1341 AN: 5158

South Asian (SAS) AF: 0.231 AC: 1115 AN: 4818

European-Finnish (FIN) AF: 0.308 AC: 3258 AN: 10574

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21922 AN: 67934

Other (OTH) AF: 0.358 AC: 755 AN: 2106

Alfa AF: 0.340 Hom.: 1117

Bravo AF: 0.381

Asia WGS AF: 0.262 AC: 914 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.52
PhyloP100		0.25
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: rs1544604; hg19: chr16-9887244;