16-9841209-T-G

Variant names:

• chr16-9841209-T-G
• rs6497540
• NM_001134407.3:c.1329-105A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001134407.3(GRIN2A):​c.1329-105A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 986,132 control chromosomes in the GnomAD database, including 67,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (11685 hom., cov: 32)
  • Exomes 𝑓: 0.35 (56201 hom.)
• Consequence: GRIN2A NM_001134407.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.328
• Publications: 12 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=-0.83).
• BP6: Variant 16-9841209-T-G is Benign according to our data. Variant chr16-9841209-T-G is described in ClinVar as Benign. ClinVar VariationId is 674884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.1329-105A>C		intron_variant	Intron 5 of 12	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.1329-105A>C		intron_variant	Intron 5 of 12	1	NM_001134407.3	ENSP00000332549.3

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58134 AN: 151866 Hom.: 11672 Cov.: 32

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.355 AC: 296095 AN: 834146 Hom.: 56201 AF XY: 0.350 AC XY: 152890 AN XY: 436370

African (AFR) AF: 0.473 AC: 9934 AN: 21004

American (AMR) AF: 0.268 AC: 10327 AN: 38586

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 7963 AN: 21942

East Asian (EAS) AF: 0.0665 AC: 2302 AN: 34606

South Asian (SAS) AF: 0.243 AC: 17227 AN: 70786

European-Finnish (FIN) AF: 0.341 AC: 15931 AN: 46702

Middle Eastern (MID) AF: 0.343 AC: 1541 AN: 4496

European-Non Finnish (NFE) AF: 0.389 AC: 216615 AN: 556406

Other (OTH) AF: 0.360 AC: 14255 AN: 39618

GnomAD4 genome AF: 0.383 AC: 58170 AN: 151986 Hom.: 11685 Cov.: 32 AF XY: 0.372 AC XY: 27595 AN XY: 74266

African (AFR) AF: 0.467 AC: 19356 AN: 41472

American (AMR) AF: 0.313 AC: 4776 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1260 AN: 3464

East Asian (EAS) AF: 0.0743 AC: 384 AN: 5166

South Asian (SAS) AF: 0.218 AC: 1047 AN: 4812

European-Finnish (FIN) AF: 0.334 AC: 3525 AN: 10562

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26528 AN: 67930

Other (OTH) AF: 0.381 AC: 806 AN: 2116

Alfa AF: 0.386 Hom.: 37384

Bravo AF: 0.385

Asia WGS AF: 0.171 AC: 599 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.54
PhyloP100		-0.33
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: rs6497540; hg19: chr16-9935066; COSMIC: COSV58043190;