chr16-9822347-C-G

Variant names:

• chr16-9822347-C-G
• rs9806806
• NM_001134407.3:c.2085G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001134407.3(GRIN2A):​c.2085G>C​(p.Arg695Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,609,860 control chromosomes in the GnomAD database, including 62,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R695R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (8993 hom., cov: 32)
  • Exomes 𝑓: 0.26 (53564 hom.)
• Consequence: GRIN2A NM_001134407.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0880
• Publications: 28 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-9822347-C-G is Benign according to our data. Variant chr16-9822347-C-G is described in ClinVar as Benign. ClinVar VariationId is 129192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.088 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.2085G>C	p.Arg695Arg	synonymous_variant	Exon 10 of 13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.2085G>C	p.Arg695Arg	synonymous_variant	Exon 10 of 13	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49108 AN: 151794 Hom.: 8966 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0740

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.256 AC: 64335 AN: 251274 AF XY: 0.252

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.0719

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.264 AC: 384955 AN: 1457946 Hom.: 53564 Cov.: 31 AF XY: 0.262 AC XY: 190052 AN XY: 725546

African (AFR) AF: 0.509 AC: 16997 AN: 33386

American (AMR) AF: 0.221 AC: 9873 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7569 AN: 26102

East Asian (EAS) AF: 0.0680 AC: 2698 AN: 39674

South Asian (SAS) AF: 0.203 AC: 17516 AN: 86184

European-Finnish (FIN) AF: 0.265 AC: 14130 AN: 53416

Middle Eastern (MID) AF: 0.238 AC: 1371 AN: 5766

European-Non Finnish (NFE) AF: 0.269 AC: 298413 AN: 1108430

Other (OTH) AF: 0.272 AC: 16388 AN: 60276

GnomAD4 genome AF: 0.324 AC: 49169 AN: 151914 Hom.: 8993 Cov.: 32 AF XY: 0.318 AC XY: 23577 AN XY: 74244

African (AFR) AF: 0.501 AC: 20750 AN: 41396

American (AMR) AF: 0.256 AC: 3901 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 996 AN: 3462

East Asian (EAS) AF: 0.0742 AC: 383 AN: 5162

South Asian (SAS) AF: 0.192 AC: 923 AN: 4812

European-Finnish (FIN) AF: 0.258 AC: 2721 AN: 10548

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18497 AN: 67958

Other (OTH) AF: 0.311 AC: 656 AN: 2108

Alfa AF: 0.247 Hom.: 1520

Bravo AF: 0.330

EpiCase AF: 0.267

EpiControl AF: 0.263

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Oct 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Oct 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 36. Only high quality variants are reported. -

Landau-Kleffner syndrome Benign:2

Jan 12, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Dec 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.3
DANN	Benign	0.62
PhyloP100		-0.088
Mutation Taster		=91/9	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: rs9806806; hg19: chr16-9916204; COSMIC: COSV58033242;