16-9754753-A-G

Position:

• chr16-9754753-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134407.3(GRIN2A):​c.*8396T>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 0.00305 in 219,516 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (1 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.32

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-9754753-A-G is Benign according to our data. Variant chr16-9754753-A-G is described in ClinVar as [Benign]. Clinvar id is 321473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00298 (454/152336) while in subpopulation NFE AF= 0.00504 (343/68016). AF 95% confidence interval is 0.0046. There are 2 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*8396T>C		3_prime_UTR_variant	13/13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.*8396T>C		3_prime_UTR_variant	13/13	1	NM_001134407.3	ENSP00000332549	P1
GRIN2A	ENST00000396573.6	c.*8396T>C		3_prime_UTR_variant	14/14	1		ENSP00000379818	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00320 AC: 215 AN: 67180 Hom.: 1 Cov.: 0 AF XY: 0.00347 AC XY: 108 AN XY: 31108

Gnomad4 AFR exome AF: 0.000638

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00445

Gnomad4 OTH exome AF: 0.00266

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152336 Hom.: 2 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74502

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00504

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00296

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

GRIN2A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.56

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: rs192548671; hg19: chr16-9848610;