rs1014531

chr16-9761937-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001134407.3(GRIN2A):c.*1212C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 203,760 control chromosomes in the GnomAD database, including 12,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (9038 hom., cov: 33)
  • Exomes 𝑓: 0.36 (3486 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.352

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-9761937-G-A is Benign according to our data. Variant chr16-9761937-G-A is described in ClinVar as [Benign]. Clinvar id is 321583.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.*1212C>T		3_prime_UTR_variant	13/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.*1212C>T		3_prime_UTR_variant	13/13	1	NM_001134407.3	P1
GRIN2A	ENST00000396573.6	c.*1212C>T		3_prime_UTR_variant	14/14	1		P1
GRIN2A	ENST00000535259.6	c.*1418C>T		3_prime_UTR_variant	13/13	5
GRIN2A	ENST00000674742.1	c.*1212C>T		3_prime_UTR_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51269 AN: 152046 Hom.: 9035 Cov.: 33

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.358 AC: 18459 AN: 51596 Hom.: 3486 Cov.: 0 AF XY: 0.361 AC XY: 8677 AN XY: 24066

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.337 AC: 51295 AN: 152164 Hom.: 9038 Cov.: 33 AF XY: 0.327 AC XY: 24337 AN XY: 74400

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.343

Alfa AF: 0.388 Hom.: 20253

Bravo AF: 0.337

Asia WGS AF: 0.231 AC: 806 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.81
Cadd	Benign	3.2
Dann	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs1014531; hg19: chr16-9855794;