10-111078794-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1BS2_Supporting

The NM_000681.4(ADRA2A):c.798C>G(p.Asn266Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,343,856 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N266D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 26 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 19 hom. )

Consequence

ADRA2A
NM_000681.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.608

Publications

14 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016781837).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1542/150498) while in subpopulation AFR AF = 0.0351 (1449/41330). AF 95% confidence interval is 0.0336. There are 26 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1542 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA2A	NM_000681.4 link	c.798C>G	p.Asn266Lys	missense_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.798C>G	p.Asn266Lys	missense_variant	Exon 1 of 1	6	NM_000681.4	ENSP00000280155.2		P08913

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1541

AN:

150388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000593

Gnomad OTH

AF:

0.00630

GnomAD2 exomes

AF:

0.00194

AC:

AN:

15456

AF XY:

0.00187

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.00812

Gnomad ASJ exome

AF:

0.00379

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00625

GnomAD4 exome

AF:

0.000959

AC:

1144

AN:

1193358

Hom.:

Cov.:

AF XY:

0.000849

AC XY:

490

AN XY:

577486

show subpopulations

African (AFR)

AF:

0.0383

AC:

880

AN:

22998

American (AMR)

AF:

0.00742

AC:

AN:

9166

Ashkenazi Jewish (ASJ)

AF:

0.000450

AC:

AN:

15548

East Asian (EAS)

AF:

0.00

AC:

AN:

26300

South Asian (SAS)

AF:

0.000158

AC:

AN:

44408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38768

Middle Eastern (MID)

AF:

0.00166

AC:

AN:

4826

European-Non Finnish (NFE)

AF:

0.0000661

AC:

AN:

983270

Other (OTH)

AF:

0.00227

AC:

109

AN:

48074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.0102

AC:

1542

AN:

150498

Hom.:

Cov.:

AF XY:

0.00979

AC XY:

720

AN XY:

73550

show subpopulations

African (AFR)

AF:

0.0351

AC:

1449

AN:

41330

American (AMR)

AF:

0.00477

AC:

AN:

15090

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000593

AC:

AN:

67484

Other (OTH)

AF:

0.00623

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

142

212

283

354

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:

0.000352

Hom.:

Bravo

AF:

0.0123

ExAC

AF:

0.00161

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.0

(source)

DANN

Benign

0.77

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.19

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.90

PhyloP100

-0.61

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.1

REVEL

Benign

0.19

Sift

Benign

0.30

Sift4G

Benign

0.31

Vest4

0.29

MVP

0.46

ClinPred

0.020

GERP RS

0.90

gMVP

0.33

Mutation Taster

=68/32

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over