16-9754614-T-G

Variant names:

• chr16-9754614-T-G
• rs767749
• NM_001134407.3:c.*8535A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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 -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 rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*8535A>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000330684.4	NP_001127879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4	c.*8535A>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_001134407.3	ENSP00000332549.3
GRIN2A	ENST00000396573.6	c.*8535A>C		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000379818.2

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

African (AFR) AF: 0.814 AC: 2344 AN: 2878

American (AMR) AF: 0.712 AC: 1325 AN: 1860

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 3583 AN: 3910

East Asian (EAS) AF: 0.661 AC: 6025 AN: 9120

South Asian (SAS) AF: 0.782 AC: 424 AN: 542

European-Finnish (FIN) AF: 0.722 AC: 26 AN: 36

Middle Eastern (MID) AF: 0.899 AC: 331 AN: 368

European-Non Finnish (NFE) AF: 0.849 AC: 32457 AN: 38210

Other (OTH) AF: 0.829 AC: 4334 AN: 5230

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

African (AFR) AF: 0.810 AC: 33590 AN: 41462

American (AMR) AF: 0.716 AC: 10928 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3191 AN: 3470

East Asian (EAS) AF: 0.640 AC: 3314 AN: 5178

South Asian (SAS) AF: 0.782 AC: 3760 AN: 4806

European-Finnish (FIN) AF: 0.698 AC: 7351 AN: 10534

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.848 AC: 57624 AN: 67968

Other (OTH) AF: 0.840 AC: 1776 AN: 2114

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.68
PhyloP100		0.83

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: rs767749; hg19: chr16-9848471;