chr16-10183567-G-GACACACACACACACACAC

Variant names:

• chr16-10183567-G-GACACACACACACACACAC
• rs3219790
• ENST00000784515.1:n.209+1867_209+1868insACACACACACACACACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000784515.1(ENSG00000302122):​n.209+1867_209+1868insACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.030 (155 hom., cov: 0)
• Consequence: ENSG00000302122 ENST00000784515.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 9 publications found

Genes affected

ENSG00000302122 (HGNC:):

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0297 (3721/125404) while in subpopulation NFE AF = 0.0367 (2199/59964). AF 95% confidence interval is 0.0354. There are 155 homozygotes in GnomAd4. There are 1707 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 155 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000302122	ENST00000784515.1	n.209+1867_209+1868insACACACACACACACACAC		intron_variant	Intron 1 of 2
ENSG00000302122	ENST00000784516.1	n.209+1867_209+1868insACACACACACACACACAC		intron_variant	Intron 1 of 1
ENSG00000302122	ENST00000784517.1	n.208+1867_208+1868insACACACACACACACACAC		intron_variant	Intron 1 of 2
GRIN2A	ENST00000675398.2	c.-1124_-1123insGTGTGTGTGTGTGTGTGT		upstream_gene_variant				ENSP00000502752.1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 3718 AN: 125340 Hom.: 155 Cov.: 0

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00746

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.00775

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0299

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

GnomAD4 genome AF: 0.0297 AC: 3721 AN: 125404 Hom.: 155 Cov.: 0 AF XY: 0.0287 AC XY: 1707 AN XY: 59380

African (AFR) AF: 0.0218 AC: 706 AN: 32420

American (AMR) AF: 0.0235 AC: 300 AN: 12772

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 103 AN: 3186

East Asian (EAS) AF: 0.0227 AC: 92 AN: 4044

South Asian (SAS) AF: 0.0255 AC: 84 AN: 3288

European-Finnish (FIN) AF: 0.0255 AC: 178 AN: 6994

Middle Eastern (MID) AF: 0.0126 AC: 3 AN: 238

European-Non Finnish (NFE) AF: 0.0367 AC: 2199 AN: 59964

Other (OTH) AF: 0.0295 AC: 50 AN: 1694

Alfa AF: 0.00 Hom.: 154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3219790; hg19: chr16-10277424;