NM_001134407.3:c.415-47777T>C

Variant names:

• chr16-9986328-A-G
• rs17569693
• NM_001134407.3:c.415-47777T>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.415-47777T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 152,310 control chromosomes in the GnomAD database, including 635 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 0.084 (635 hom., cov: 32)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0986 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.415-47777T>C		intron	N/A	NP_001127879.1
	GRIN2A	NM_000833.5		c.415-47777T>C		intron	N/A	NP_000824.1
	GRIN2A	NM_001134408.2		c.415-47777T>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.415-47777T>C		intron	N/A	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.415-47777T>C		intron	N/A	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.415-47777T>C		intron	N/A	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12814 AN: 152192 Hom.: 636 Cov.: 32

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0654

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

GnomAD4 genome AF: 0.0842 AC: 12821 AN: 152310 Hom.: 635 Cov.: 32 AF XY: 0.0816 AC XY: 6077 AN XY: 74478

African (AFR) AF: 0.0877 AC: 3644 AN: 41568

American (AMR) AF: 0.0502 AC: 768 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3468

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4834

European-Finnish (FIN) AF: 0.117 AC: 1235 AN: 10600

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6847 AN: 68034

Other (OTH) AF: 0.0647 AC: 137 AN: 2116

Alfa AF: 0.0841 Hom.: 624

Bravo AF: 0.0800

Asia WGS AF: 0.0100 AC: 36 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.71
PhyloP100		0.060
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: rs17569693; hg19: chr16-10080185;