16-9754396-A-G

Variant names:

• chr16-9754396-A-G
• rs182174522
• NM_001134407.3:c.*8753T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001134407.3(GRIN2A):​c.*8753T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 209,902 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0520
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-9754396-A-G is Benign according to our data. Variant chr16-9754396-A-G is described in ClinVar as [Benign]. Clinvar id is 321466.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00088 (134/152330) while in subpopulation EAS AF = 0.021 (109/5186). AF 95% confidence interval is 0.0178. There are 2 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*8753T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.*8753T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_001134407.3	ENSP00000332549.3
GRIN2A	ENST00000396573.6	c.*8753T>C		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000379818.2

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152212 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000816 AC: 47 AN: 57572 Hom.: 2 Cov.: 0 AF XY: 0.000860 AC XY: 23 AN XY: 26756

African (AFR) AF: 0.000374 AC: 1 AN: 2676

American (AMR) AF: 0.00 AC: 0 AN: 1642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3610

East Asian (EAS) AF: 0.00466 AC: 41 AN: 8804

South Asian (SAS) AF: 0.00 AC: 0 AN: 476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 336

European-Non Finnish (NFE) AF: 0.0000284 AC: 1 AN: 35184

Other (OTH) AF: 0.000832 AC: 4 AN: 4806

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152330 Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74488

African (AFR) AF: 0.000385 AC: 16 AN: 41588

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5186

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000805

Asia WGS AF: 0.00867 AC: 30 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.75
PhyloP100		0.052
Mutation Taster		=99/1	polymorphism

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: rs182174522; hg19: chr16-9848253;