16-9768699-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001134407.3(GRIN2A):c.2595+152C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 753,224 control chromosomes in the GnomAD database, including 54,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11361 hom., cov: 33)

Exomes 𝑓: 0.37 ( 42760 hom. )

Consequence

GRIN2A
NM_001134407.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.601

Publications

37 publications found

Variant links:

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

GRIN2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-9768699-G-T is Benign according to our data. Variant chr16-9768699-G-T is described in ClinVar as [Benign]. Clinvar id is 681804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2A	NM_001134407.3 link	c.2595+152C>A		intron_variant	Intron 12 of 12	ENST00000330684.4	NP_001127879.1	Q12879-1Q547U9Q59EW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2A	ENST00000330684.4 link	c.2595+152C>A		intron_variant	Intron 12 of 12	1	NM_001134407.3	ENSP00000332549.3		Q12879-1

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57901

AN:

151928

Hom.:

11356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.394

Gnomad AMI

AF:

0.382

Gnomad AMR

AF:

0.337

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.259

Gnomad FIN

AF:

0.294

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.380

GnomAD4 exome

AF:

0.368

AC:

221270

AN:

601178

Hom.:

42760

AF XY:

0.365

AC XY:

119366

AN XY:

327310

show subpopulations

African (AFR)

AF:

0.399

AC:

6722

AN:

16840

American (AMR)

AF:

0.287

AC:

11902

AN:

41432

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

8023

AN:

20064

East Asian (EAS)

AF:

0.186

AC:

6641

AN:

35652

South Asian (SAS)

AF:

0.260

AC:

17610

AN:

67826

European-Finnish (FIN)

AF:

0.307

AC:

12278

AN:

40010

Middle Eastern (MID)

AF:

0.348

AC:

1306

AN:

3754

European-Non Finnish (NFE)

AF:

0.421

AC:

144602

AN:

343568

Other (OTH)

AF:

0.380

AC:

12186

AN:

32032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

7461

14922

22382

29843

37304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.381

AC:

57940

AN:

152046

Hom.:

11361

Cov.:

AF XY:

0.369

AC XY:

27446

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.394

AC:

16334

AN:

41462

American (AMR)

AF:

0.337

AC:

5143

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1392

AN:

3470

East Asian (EAS)

AF:

0.180

AC:

932

AN:

5174

South Asian (SAS)

AF:

0.258

AC:

1242

AN:

4808

European-Finnish (FIN)

AF:

0.294

AC:

3104

AN:

10574

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.420

AC:

28520

AN:

67972

Other (OTH)

AF:

0.381

AC:

804

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1824

3649

5473

7298

9122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.405

Hom.:

38265

Bravo

AF:

0.386

Asia WGS

AF:

0.244

AC:

853

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.48

(source)

DANN

Benign

0.74

PhyloP100

-0.60

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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16-9768699-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over