16-9754614-T-G

Position:

• chr16-9754614-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134407.3(GRIN2A):​c.*8535A>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 0.81 in 214,156 control chromosomes in the GnomAD database, including 70,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49784 hom., cov: 31)
  • Exomes 𝑓: 0.82 (20954 hom.)
• Consequence: GRIN2A NM_001134407.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.834

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=-0.87).
• BP6: Variant 16-9754614-T-G is Benign according to our data. Variant chr16-9754614-T-G is described in ClinVar as [Benign]. Clinvar id is 321471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*8535A>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.*8535A>C		3_prime_UTR_variant	13/13	1	NM_001134407.3	ENSP00000332549	P1
GRIN2A	ENST00000396573.6	c.*8535A>C		3_prime_UTR_variant	14/14	1		ENSP00000379818	P1

Frequencies

GnomAD3 genomes AF: 0.806 AC: 122425 AN: 151884 Hom.: 49744 Cov.: 31

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.848

Gnomad OTH AF: 0.839

GnomAD4 exome AF: 0.818 AC: 50849 AN: 62154 Hom.: 20954 Cov.: 0 AF XY: 0.821 AC XY: 23610 AN XY: 28772

Gnomad4 AFR exome AF: 0.814

Gnomad4 AMR exome AF: 0.712

Gnomad4 ASJ exome AF: 0.916

Gnomad4 EAS exome AF: 0.661

Gnomad4 SAS exome AF: 0.782

Gnomad4 FIN exome AF: 0.722

Gnomad4 NFE exome AF: 0.849

Gnomad4 OTH exome AF: 0.829

GnomAD4 genome AF: 0.806 AC: 122520 AN: 152002 Hom.: 49784 Cov.: 31 AF XY: 0.796 AC XY: 59159 AN XY: 74300

Gnomad4 AFR AF: 0.810

Gnomad4 AMR AF: 0.716

Gnomad4 ASJ AF: 0.920

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.782

Gnomad4 FIN AF: 0.698

Gnomad4 NFE AF: 0.848

Gnomad4 OTH AF: 0.840

Alfa AF: 0.825 Hom.: 6335

Bravo AF: 0.805

Asia WGS AF: 0.739 AC: 2569 AN: 3476

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.68

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: rs767749; hg19: chr16-9848471;