rs1420040

Variant names:

• chr16-9756540-A-G
• rs1420040
• NM_001134407.3:c.*6609T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-9756540-A-G
• chr16-9756540-A-T

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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.20
• Publications: 20 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=-0.91).
• BP6: Variant 16-9756540-A-G is Benign according to our data. Variant chr16-9756540-A-G is described in ClinVar as Benign. ClinVar VariationId is 321501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3	c.*6609T>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.*6609T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_001134407.3	ENSP00000332549.3
GRIN2A	ENST00000396573.6	c.*6609T>C		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000379818.2

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

African (AFR) AF: 0.353 AC: 971 AN: 2748

American (AMR) AF: 0.387 AC: 695 AN: 1794

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 2079 AN: 3788

East Asian (EAS) AF: 0.459 AC: 4208 AN: 9160

South Asian (SAS) AF: 0.568 AC: 299 AN: 526

European-Finnish (FIN) AF: 0.313 AC: 15 AN: 48

Middle Eastern (MID) AF: 0.563 AC: 198 AN: 352

European-Non Finnish (NFE) AF: 0.444 AC: 16244 AN: 36586

Other (OTH) AF: 0.442 AC: 2205 AN: 4990

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

African (AFR) AF: 0.343 AC: 14198 AN: 41436

American (AMR) AF: 0.375 AC: 5727 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1867 AN: 3468

East Asian (EAS) AF: 0.445 AC: 2292 AN: 5154

South Asian (SAS) AF: 0.555 AC: 2660 AN: 4796

European-Finnish (FIN) AF: 0.409 AC: 4324 AN: 10578

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30343 AN: 67934

Other (OTH) AF: 0.446 AC: 940 AN: 2106

Alfa AF: 0.437 Hom.: 58044

Bravo AF: 0.404

Asia WGS AF: 0.495 AC: 1720 AN: 3478

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	-0.91
CADD	Benign	6.0
DANN	Benign	0.70
PhyloP100		1.2

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