16-10174473-T-C

Variant names:

• chr16-10174473-T-C
• rs1650420
• NM_001134407.3:c.414+5525A>G

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+5525A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 152,058 control chromosomes in the GnomAD database, including 26,453 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 0.58 (26453 hom., cov: 32)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 20 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 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.414+5525A>G		intron	N/A	NP_001127879.1	Q12879-1
	GRIN2A	NM_000833.5		c.414+5525A>G		intron	N/A	NP_000824.1	Q12879-1
	GRIN2A	NM_001134408.2		c.414+5525A>G		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.414+5525A>G		intron	N/A	ENSP00000332549.3	Q12879-1
	GRIN2A	ENST00000396573.6	TSL:1	c.414+5525A>G		intron	N/A	ENSP00000379818.2	Q12879-1
	GRIN2A	ENST00000562109.5	TSL:1	c.414+5525A>G		intron	N/A	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88569 AN: 151940 Hom.: 26443 Cov.: 32

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.593

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

GnomAD4 genome AF: 0.583 AC: 88611 AN: 152058 Hom.: 26453 Cov.: 32 AF XY: 0.581 AC XY: 43183 AN XY: 74314

African (AFR) AF: 0.483 AC: 20031 AN: 41438

American (AMR) AF: 0.545 AC: 8331 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2270 AN: 3472

East Asian (EAS) AF: 0.451 AC: 2334 AN: 5180

South Asian (SAS) AF: 0.480 AC: 2313 AN: 4820

European-Finnish (FIN) AF: 0.694 AC: 7332 AN: 10570

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 44016 AN: 67986

Other (OTH) AF: 0.593 AC: 1253 AN: 2114

Alfa AF: 0.623 Hom.: 112711

Bravo AF: 0.570

Asia WGS AF: 0.497 AC: 1730 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.55
DANN	Benign	0.42
PhyloP100		-1.2
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: rs1650420; hg19: chr16-10268330;