16-9849809-C-T

Variant names:

• chr16-9849809-C-T
• rs2229193
• NM_001134407.3:c.1275G>A

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.1275G>A​(p.Leu425Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,613,150 control chromosomes in the GnomAD database, including 61,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5829 hom., cov: 31)
  • Exomes 𝑓: 0.27 (56057 hom.)
• Consequence: GRIN2A NM_001134407.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.484
• Publications: 36 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=-0.36).
• BP6: Variant 16-9849809-C-T is Benign according to our data. Variant chr16-9849809-C-T is described in ClinVar as Benign. ClinVar VariationId is 129190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	NM_001134407.3	MANE Select	c.1275G>A	p.Leu425Leu	synonymous	Exon 5 of 13	NP_001127879.1
	GRIN2A	NM_000833.5		c.1275G>A	p.Leu425Leu	synonymous	Exon 6 of 14	NP_000824.1
	GRIN2A	NM_001134408.2		c.1275G>A	p.Leu425Leu	synonymous	Exon 5 of 14	NP_001127880.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.1275G>A	p.Leu425Leu	synonymous	Exon 5 of 13	ENSP00000332549.3
	GRIN2A	ENST00000396573.6	TSL:1	c.1275G>A	p.Leu425Leu	synonymous	Exon 6 of 14	ENSP00000379818.2
	GRIN2A	ENST00000562109.5	TSL:1	c.1275G>A	p.Leu425Leu	synonymous	Exon 5 of 14	ENSP00000454998.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41381 AN: 151790 Hom.: 5824 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.0680

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.249 AC: 62527 AN: 251348 AF XY: 0.250

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.0665

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.273 AC: 398803 AN: 1461242 Hom.: 56057 Cov.: 36 AF XY: 0.272 AC XY: 197611 AN XY: 726968

African (AFR) AF: 0.302 AC: 10097 AN: 33468

American (AMR) AF: 0.206 AC: 9228 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7628 AN: 26134

East Asian (EAS) AF: 0.0616 AC: 2446 AN: 39690

South Asian (SAS) AF: 0.222 AC: 19132 AN: 86238

European-Finnish (FIN) AF: 0.265 AC: 14162 AN: 53418

Middle Eastern (MID) AF: 0.227 AC: 1312 AN: 5768

European-Non Finnish (NFE) AF: 0.287 AC: 318556 AN: 1111430

Other (OTH) AF: 0.269 AC: 16242 AN: 60374

GnomAD4 genome AF: 0.272 AC: 41392 AN: 151908 Hom.: 5829 Cov.: 31 AF XY: 0.266 AC XY: 19715 AN XY: 74226

African (AFR) AF: 0.299 AC: 12382 AN: 41412

American (AMR) AF: 0.235 AC: 3581 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1006 AN: 3468

East Asian (EAS) AF: 0.0682 AC: 352 AN: 5162

South Asian (SAS) AF: 0.203 AC: 975 AN: 4796

European-Finnish (FIN) AF: 0.257 AC: 2705 AN: 10544

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19452 AN: 67944

Other (OTH) AF: 0.263 AC: 556 AN: 2112

Alfa AF: 0.281 Hom.: 14896

Bravo AF: 0.272

Asia WGS AF: 0.143 AC: 503 AN: 3476

EpiCase AF: 0.283

EpiControl AF: 0.280

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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.

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.

Landau-Kleffner syndrome Benign:2

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.3
DANN	Benign	0.80
PhyloP100		0.48
Mutation Taster		=97/3	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: rs2229193; hg19: chr16-9943666; COSMIC: COSV58020811; COSMIC: COSV58020811;