dbSNP rs1800035: ADRA2A:p.Asn266Lys (chr10-111078794-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000681.4(ADRA2A):c.798C>A(p.Asn266Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000838 in 1,193,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: not found (cov: 33)

Exomes 𝑓: 8.4e-7 ( 0 hom. )

Consequence

ADRA2A
NM_000681.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.608

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27067065).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.38e-7

AC:

AN:

1193358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

577486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22998

American (AMR)

AF:

0.00

AC:

AN:

9166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15548

East Asian (EAS)

AF:

0.00

AC:

AN:

26300

South Asian (SAS)

AF:

0.00

AC:

AN:

44408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4826

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

983270

Other (OTH)

AF:

0.00

AC:

AN:

48074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.7

(source)

DANN

Benign

0.91

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.36

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.92

PhyloP100

-0.61

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Benign

0.30

Sift4G

Benign

0.31

Vest4

0.29

MVP

0.46

ClinPred

0.25

GERP RS

0.90

gMVP

0.33

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over