dbSNP rs1800038: ADRA2A:p.Arg380Arg (chr10-111079134-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_000681.4(ADRA2A):c.1138C>A(p.Arg380Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,602,504 control chromosomes in the GnomAD database, including 4,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.053 ( 610 hom., cov: 33)

Exomes 𝑓: 0.026 ( 3569 hom. )

Consequence

ADRA2A
NM_000681.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.374

Publications

13 publications found

Variant links:

Genes affected

ADRA2A (HGNC:281): (adrenoceptor alpha 2A) Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. The alpha-2-adrenergic receptors are a type of adrenergic receptors (for adrenaline or epinephrine), which inhibit adenylate cyclase. These receptors include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. They are involved in regulating the release of neurotransmitter molecules from sympathetic nerves and from adrenergic neurons in the central nervous system. The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. Studies in mouse revealed that both the alpha2A and alpha2C receptor subtypes were required for presynaptic transmitter release from the sympathetic nervous system in the heart and from central noradrenergic neurons. The alpha-2-adrenergic receptors are also involved in catecholamine signaling by extracellular regulated protein kinase 1 and 2 (ERK1/2) pathways. A clear association between the alpha-2-adrenergic receptor and disease has not been yet established. [provided by RefSeq, Sep 2019]

ADRA2A Gene-Disease associations (from GenCC):

lipodystrophy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
lipodystrophy, familial partial, type 8
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ADRA2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP7

Synonymous conserved (PhyloP=0.374 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA2A	NM_000681.4 link	c.1138C>A	p.Arg380Arg	synonymous_variant	Exon 1 of 1	ENST00000280155.4	NP_000672.3	P08913

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA2A	ENST00000280155.4 link	c.1138C>A	p.Arg380Arg	synonymous_variant	Exon 1 of 1	6	NM_000681.4	ENSP00000280155.2		P08913

Frequencies

GnomAD3 genomes

AF:

0.0528

AC:

8033

AN:

152024

Hom.:

601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0752

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.306

Gnomad SAS

AF:

0.0751

Gnomad FIN

AF:

0.0170

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00540

Gnomad OTH

AF:

0.0547

GnomAD2 exomes

AF:

0.0738

AC:

17900

AN:

242440

AF XY:

0.0654

show subpopulations

Gnomad AFR exome

AF:

0.0797

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.00186

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.00581

Gnomad OTH exome

AF:

0.0432

GnomAD4 exome

AF:

0.0263

AC:

38074

AN:

1450366

Hom.:

3569

Cov.:

AF XY:

0.0262

AC XY:

18841

AN XY:

720282

show subpopulations

African (AFR)

AF:

0.0779

AC:

2589

AN:

33224

American (AMR)

AF:

0.215

AC:

9535

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.00109

AC:

AN:

25778

East Asian (EAS)

AF:

0.302

AC:

11901

AN:

39446

South Asian (SAS)

AF:

0.0653

AC:

5592

AN:

85636

European-Finnish (FIN)

AF:

0.0152

AC:

763

AN:

50212

Middle Eastern (MID)

AF:

0.0218

AC:

125

AN:

5734

European-Non Finnish (NFE)

AF:

0.00464

AC:

5128

AN:

1106040

Other (OTH)

AF:

0.0402

AC:

2413

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1867

3734

5600

7467

9334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.0530

AC:

8065

AN:

152138

Hom.:

610

Cov.:

AF XY:

0.0580

AC XY:

4315

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0752

AC:

3127

AN:

41556

American (AMR)

AF:

0.152

AC:

2330

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.305

AC:

1575

AN:

5162

South Asian (SAS)

AF:

0.0753

AC:

364

AN:

4832

European-Finnish (FIN)

AF:

0.0170

AC:

180

AN:

10560

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00540

AC:

367

AN:

67964

Other (OTH)

AF:

0.0546

AC:

115

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

362

724

1086

1448

1810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0165

Hom.:

Bravo

AF:

0.0650

Asia WGS

AF:

0.179

AC:

619

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.8

(source)

DANN

Benign

0.96

PhyloP100

0.37

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over