Genetic Variant NM_001134407.3:c.2190C>T (chr16-9798443-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001134407.3(GRIN2A):c.2190C>T(p.Tyr730Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 1,613,968 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 46 hom. )

Consequence

GRIN2A
NM_001134407.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0880

Publications

6 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, 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:

ENSG00000283221 (HGNC:):

ENSG00000283221 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 16-9798443-G-A is Benign according to our data. Variant chr16-9798443-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.088 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00738 (1124/152262) while in subpopulation AFR AF = 0.0109 (451/41554). AF 95% confidence interval is 0.01. There are 2 homozygotes in GnomAd4. There are 555 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134407.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2A	NM_001134407.3	MANE Select	c.2190C>T	p.Tyr730Tyr	synonymous	Exon 11 of 13	NP_001127879.1	Q12879-1
GRIN2A	NM_000833.5		c.2190C>T	p.Tyr730Tyr	synonymous	Exon 12 of 14	NP_000824.1	Q12879-1
GRIN2A	NM_001134408.2		c.2190C>T	p.Tyr730Tyr	synonymous	Exon 11 of 14	NP_001127880.1	Q12879-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN2A	ENST00000330684.4	TSL:1 MANE Select	c.2190C>T	p.Tyr730Tyr	synonymous	Exon 11 of 13	ENSP00000332549.3	Q12879-1
GRIN2A	ENST00000396573.6	TSL:1	c.2190C>T	p.Tyr730Tyr	synonymous	Exon 12 of 14	ENSP00000379818.2	Q12879-1
GRIN2A	ENST00000562109.5	TSL:1	c.2190C>T	p.Tyr730Tyr	synonymous	Exon 11 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes

AF:

0.00737

AC:

1121

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00681

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00630

AC:

1580

AN:

250926

AF XY:

0.00658

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00671

GnomAD4 exome

AF:

0.00619

AC:

9044

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00641

AC XY:

4662

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0106

AC:

355

AN:

33478

American (AMR)

AF:

0.00208

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

373

AN:

26134

East Asian (EAS)

AF:

0.000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.00756

AC:

652

AN:

86256

European-Finnish (FIN)

AF:

0.00756

AC:

404

AN:

53412

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00607

AC:

6748

AN:

1111872

Other (OTH)

AF:

0.00618

AC:

373

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

443

885

1328

1770

2213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00738

AC:

1124

AN:

152262

Hom.:

Cov.:

AF XY:

0.00746

AC XY:

555

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0109

AC:

451

AN:

41554

American (AMR)

AF:

0.00268

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00395

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00681

AC:

463

AN:

68016

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00750

Hom.:

Bravo

AF:

0.00690

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00758

EpiControl

AF:

0.00700

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Landau-Kleffner syndrome (5)

not provided (3)

not specified (2)

GRIN2A-related complex neurodevelopmental disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.8

(source)

DANN

Benign

0.20

PhyloP100

0.088

Mutation Taster

=100/0

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over