Genetic Variant NM_001083619.3:c.687T>C (chr4-157317678-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001083619.3(GRIA2):c.687T>C(p.His229His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,208,880 control chromosomes in the GnomAD database, including 246,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30113 hom., cov: 32)

Exomes 𝑓: 0.63 ( 215989 hom. )

Consequence

GRIA2
NM_001083619.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.58

Publications

24 publications found

Variant links:

Genes affected

GRIA2 (HGNC:4572): (glutamate ionotropic receptor AMPA type subunit 2) Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. These channels are assembled from 4 related subunits, GRIA1-4. The subunit encoded by this gene (GRIA2) is subject to RNA editing (CAG->CGG; Q->R) within the second transmembrane domain, which is thought to render the channel impermeable to Ca(2+). Human and animal studies suggest that pre-mRNA editing is essential for brain function, and defective GRIA2 RNA editing at the Q/R site may be relevant to amyotrophic lateral sclerosis (ALS) etiology. Alternative splicing, resulting in transcript variants encoding different isoforms, (including the flip and flop isoforms that vary in their signal transduction properties), has been noted for this gene. [provided by RefSeq, Jul 2008]

GRIA2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with language impairment and behavioral abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P, Illumina

GRIA2 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=-0.52).

BP6

Variant 4-157317678-T-C is Benign according to our data. Variant chr4-157317678-T-C is described in ClinVar as Benign. ClinVar VariationId is 1266895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.59 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083619.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIA2	NM_001083619.3	MANE Select	c.687T>C	p.His229His	synonymous	Exon 5 of 16	NP_001077088.2
GRIA2	NM_000826.6		c.687T>C	p.His229His	synonymous	Exon 5 of 16	NP_000817.5
GRIA2	NM_001083620.3		c.546T>C	p.His182His	synonymous	Exon 5 of 16	NP_001077089.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIA2	ENST00000264426.14	TSL:1 MANE Select	c.687T>C	p.His229His	synonymous	Exon 5 of 16	ENSP00000264426.9
GRIA2	ENST00000296526.12	TSL:1	c.687T>C	p.His229His	synonymous	Exon 5 of 16	ENSP00000296526.7
GRIA2	ENST00000393815.6	TSL:1	c.546T>C	p.His182His	synonymous	Exon 5 of 16	ENSP00000377403.2

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94767

AN:

151796

Hom.:

30101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.513

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.642

Gnomad EAS

AF:

0.821

Gnomad SAS

AF:

0.724

Gnomad FIN

AF:

0.647

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.623

GnomAD2 exomes

AF:

0.674

AC:

161742

AN:

240144

AF XY:

0.671

show subpopulations

Gnomad AFR exome

AF:

0.500

Gnomad AMR exome

AF:

0.793

Gnomad ASJ exome

AF:

0.650

Gnomad EAS exome

AF:

0.812

Gnomad FIN exome

AF:

0.642

Gnomad NFE exome

AF:

0.637

Gnomad OTH exome

AF:

0.646

GnomAD4 exome

AF:

0.633

AC:

669281

AN:

1056966

Hom.:

215989

Cov.:

AF XY:

0.637

AC XY:

345672

AN XY:

542972

show subpopulations

African (AFR)

AF:

0.487

AC:

12615

AN:

25916

American (AMR)

AF:

0.782

AC:

32969

AN:

42168

Ashkenazi Jewish (ASJ)

AF:

0.640

AC:

14755

AN:

23062

East Asian (EAS)

AF:

0.839

AC:

30683

AN:

36574

South Asian (SAS)

AF:

0.712

AC:

52099

AN:

73224

European-Finnish (FIN)

AF:

0.640

AC:

33143

AN:

51768

Middle Eastern (MID)

AF:

0.578

AC:

2881

AN:

4984

European-Non Finnish (NFE)

AF:

0.612

AC:

460943

AN:

752926

Other (OTH)

AF:

0.630

AC:

29193

AN:

46344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

8961

17923

26884

35846

44807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10336

20672

31008

41344

51680

<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:

0.624

AC:

94811

AN:

151914

Hom.:

30113

Cov.:

AF XY:

0.627

AC XY:

46563

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.513

AC:

21235

AN:

41408

American (AMR)

AF:

0.711

AC:

10845

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.642

AC:

2223

AN:

3462

East Asian (EAS)

AF:

0.822

AC:

4244

AN:

5164

South Asian (SAS)

AF:

0.722

AC:

3482

AN:

4820

European-Finnish (FIN)

AF:

0.647

AC:

6808

AN:

10530

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.647

AC:

43966

AN:

67958

Other (OTH)

AF:

0.624

AC:

1320

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1792

3584

5376

7168

8960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<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:

0.628

Hom.:

13748

Bravo

AF:

0.622

Asia WGS

AF:

0.730

AC:

2530

AN:

3464

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

May 11, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.3

(source)

DANN

Benign

0.61

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over