16-9931458-G-A

Variant names:

• chr16-9931458-G-A
• rs4782053
• NM_001134407.3:c.1007+6501C>T

Variant summary

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

The NM_001134407.3(GRIN2A):​c.1007+6501C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 152,050 control chromosomes in the GnomAD database, including 38,032 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 0.69 (38032 hom., cov: 31)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	NM_001134407.3	MANE Select	c.1007+6501C>T		intron	N/A	NP_001127879.1	Q12879-1
	GRIN2A	NM_000833.5		c.1007+6501C>T		intron	N/A	NP_000824.1	Q12879-1
	GRIN2A	NM_001134408.2		c.1007+6501C>T		intron	N/A	NP_001127880.1	Q12879-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.1007+6501C>T		intron	N/A	ENSP00000332549.3	Q12879-1
	GRIN2A	ENST00000396573.6	TSL:1	c.1007+6501C>T		intron	N/A	ENSP00000379818.2	Q12879-1
	GRIN2A	ENST00000562109.5	TSL:1	c.1007+6501C>T		intron	N/A	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104798 AN: 151932 Hom.: 37980 Cov.: 31

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.690 AC: 104914 AN: 152050 Hom.: 38032 Cov.: 31 AF XY: 0.683 AC XY: 50760 AN XY: 74310

African (AFR) AF: 0.864 AC: 35859 AN: 41514

American (AMR) AF: 0.565 AC: 8609 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2149 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1062 AN: 5156

South Asian (SAS) AF: 0.390 AC: 1874 AN: 4810

European-Finnish (FIN) AF: 0.789 AC: 8348 AN: 10580

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44929 AN: 67952

Other (OTH) AF: 0.660 AC: 1396 AN: 2114

Alfa AF: 0.686 Hom.: 8241

Bravo AF: 0.687

Asia WGS AF: 0.328 AC: 1144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.80
DANN	Benign	0.65
PhyloP100		-0.18
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: rs4782053; hg19: chr16-10025315;