Genetic Variant NM_000681.4:c.736C>A (chr10-111078732-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.736C>A(p.Pro246Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P246A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ADRA2A
NM_000681.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.24

Publications

1 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:

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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=0.34347925).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000681.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	NM_000681.4	MANE Select	c.736C>A	p.Pro246Thr	missense	Exon 1 of 1	NP_000672.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	ENST00000280155.4	TSL:6 MANE Select	c.736C>A	p.Pro246Thr	missense	Exon 1 of 1	ENSP00000280155.2	P08913

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.50e-7

AC:

AN:

1333718

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

654050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27870

American (AMR)

AF:

0.0000408

AC:

AN:

24528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19990

East Asian (EAS)

AF:

0.00

AC:

AN:

34264

South Asian (SAS)

AF:

0.00

AC:

AN:

64270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1055582

Other (OTH)

AF:

0.00

AC:

AN:

54584

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.88

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.65

PhyloP100

2.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Benign

0.082

Sift4G

Uncertain

0.045

Vest4

0.20

MVP

0.78

ClinPred

0.79

GERP RS

3.9

gMVP

0.68

Mutation Taster

=66/34

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over