dbSNP rs9806806: GRIN2A:p.Arg695Arg (chr16-9822347-C-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001134407.3(GRIN2A):c.2085G>C(p.Arg695Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,609,860 control chromosomes in the GnomAD database, including 62,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R695R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 8993 hom., cov: 32)

Exomes 𝑓: 0.26 ( 53564 hom. )

Consequence

GRIN2A
NM_001134407.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0880

Publications

28 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 16-9822347-C-G is Benign according to our data. Variant chr16-9822347-C-G is described in ClinVar as Benign. ClinVar VariationId is 129192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.088 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

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.2085G>C	p.Arg695Arg	synonymous	Exon 10 of 13	NP_001127879.1	Q12879-1
GRIN2A	NM_000833.5		c.2085G>C	p.Arg695Arg	synonymous	Exon 11 of 14	NP_000824.1	Q12879-1
GRIN2A	NM_001134408.2		c.2085G>C	p.Arg695Arg	synonymous	Exon 10 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.2085G>C	p.Arg695Arg	synonymous	Exon 10 of 13	ENSP00000332549.3	Q12879-1
GRIN2A	ENST00000396573.6	TSL:1	c.2085G>C	p.Arg695Arg	synonymous	Exon 11 of 14	ENSP00000379818.2	Q12879-1
GRIN2A	ENST00000562109.5	TSL:1	c.2085G>C	p.Arg695Arg	synonymous	Exon 10 of 14	ENSP00000454998.1	Q12879-2

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49108

AN:

151794

Hom.:

8966

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.288

Gnomad EAS

AF:

0.0740

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.207

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.313

GnomAD2 exomes

AF:

0.256

AC:

64335

AN:

251274

AF XY:

0.252

show subpopulations

Gnomad AFR exome

AF:

0.503

Gnomad AMR exome

AF:

0.215

Gnomad ASJ exome

AF:

0.293

Gnomad EAS exome

AF:

0.0719

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.263

GnomAD4 exome

AF:

0.264

AC:

384955

AN:

1457946

Hom.:

53564

Cov.:

AF XY:

0.262

AC XY:

190052

AN XY:

725546

show subpopulations

African (AFR)

AF:

0.509

AC:

16997

AN:

33386

American (AMR)

AF:

0.221

AC:

9873

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

7569

AN:

26102

East Asian (EAS)

AF:

0.0680

AC:

2698

AN:

39674

South Asian (SAS)

AF:

0.203

AC:

17516

AN:

86184

European-Finnish (FIN)

AF:

0.265

AC:

14130

AN:

53416

Middle Eastern (MID)

AF:

0.238

AC:

1371

AN:

5766

European-Non Finnish (NFE)

AF:

0.269

AC:

298413

AN:

1108430

Other (OTH)

AF:

0.272

AC:

16388

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

13776

27552

41328

55104

68880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9872

19744

29616

39488

49360

<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:

0.324

AC:

49169

AN:

151914

Hom.:

8993

Cov.:

AF XY:

0.318

AC XY:

23577

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.501

AC:

20750

AN:

41396

American (AMR)

AF:

0.256

AC:

3901

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

996

AN:

3462

East Asian (EAS)

AF:

0.0742

AC:

383

AN:

5162

South Asian (SAS)

AF:

0.192

AC:

923

AN:

4812

European-Finnish (FIN)

AF:

0.258

AC:

2721

AN:

10548

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.272

AC:

18497

AN:

67958

Other (OTH)

AF:

0.311

AC:

656

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1590

3180

4770

6360

7950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.247

Hom.:

1520

Bravo

AF:

0.330

EpiCase

AF:

0.267

EpiControl

AF:

0.263

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Landau-Kleffner syndrome (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.3

(source)

DANN

Benign

0.62

PhyloP100

-0.088

Mutation Taster

=91/9

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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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