rs1420040

chr16-9756540-A-Gchr16-9756540-A-T

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.*6609T>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 0.424 in 211,944 control chromosomes in the GnomAD database, including 19,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13289 hom., cov: 31)
  • Exomes 𝑓: 0.45 (6117 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20

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=-0.91).
• BP6: Variant 16-9756540-A-G is Benign according to our data. Variant chr16-9756540-A-G is described in ClinVar as [Benign]. Clinvar id is 321501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN2A	NM_001134407.3	c.*6609T>C		3_prime_UTR_variant	13/13	ENST00000330684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN2A	ENST00000330684.4	c.*6609T>C		3_prime_UTR_variant	13/13	1	NM_001134407.3	P1
GRIN2A	ENST00000396573.6	c.*6609T>C		3_prime_UTR_variant	14/14	1		P1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62867 AN: 151834 Hom.: 13281 Cov.: 31

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.446

GnomAD4 exome AF: 0.449 AC: 26914 AN: 59992 Hom.: 6117 Cov.: 0 AF XY: 0.448 AC XY: 12489 AN XY: 27848

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.459

Gnomad4 SAS exome AF: 0.568

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.442

GnomAD4 genome AF: 0.414 AC: 62899 AN: 151952 Hom.: 13289 Cov.: 31 AF XY: 0.417 AC XY: 30971 AN XY: 74260

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.555

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.446

Alfa AF: 0.443 Hom.: 26481

Bravo AF: 0.404

Asia WGS AF: 0.495 AC: 1720 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	-0.91
Cadd	Benign	6.0
Dann	Benign	0.70

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: rs1420040; hg19: chr16-9850397; COSMIC: COSV105331350;