10-111078792-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_000681.4(ADRA2A):ā€‹c.796A>Gā€‹(p.Asn266Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,382,858 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N266K) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00017 ( 0 hom., cov: 33)
Exomes š‘“: 0.00011 ( 4 hom. )

Consequence

ADRA2A
NM_000681.4 missense

Scores

2
1
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.017390251).
BS2
High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes 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/exons MANE UniProt
ADRA2ANM_000681.4 linkuse as main transcriptc.796A>G p.Asn266Asp missense_variant 1/1 ENST00000280155.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADRA2AENST00000280155.4 linkuse as main transcriptc.796A>G p.Asn266Asp missense_variant 1/1 NM_000681.4 P1

Frequencies

GnomAD3 genomes
AF:
0.000173
AC:
26
AN:
150326
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000194
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00353
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000899
AC:
2
AN:
22236
Hom.:
0
AF XY:
0.0000862
AC XY:
1
AN XY:
11598
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00234
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000114
AC:
141
AN:
1232422
Hom.:
4
Cov.:
31
AF XY:
0.000175
AC XY:
105
AN XY:
598884
show subpopulations
Gnomad4 AFR exome
AF:
0.000171
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00243
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000199
Gnomad4 OTH exome
AF:
0.000160
GnomAD4 genome
AF:
0.000173
AC:
26
AN:
150436
Hom.:
0
Cov.:
33
AF XY:
0.000204
AC XY:
15
AN XY:
73524
show subpopulations
Gnomad4 AFR
AF:
0.000194
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00353
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.000159
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ADRA2A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 18, 2023The ADRA2A c.796A>G variant is predicted to result in the amino acid substitution p.Asn266Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.23% of alleles in individuals of South Asian descent (2 of 856 alleles), although it is less common in or absent from other populations in gnomAD (http://gnomad.broadinstitute.org/variant/10-112838550-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.083
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
20
DANN
Benign
0.76
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.81
D
M_CAP
Pathogenic
0.41
D
MetaRNN
Benign
0.017
T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.99
D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.14
Sift
Benign
0.18
T
Sift4G
Benign
0.19
T
Vest4
0.28
MVP
0.35
ClinPred
0.19
T
GERP RS
2.8
gMVP
0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs566589780; hg19: chr10-112838550; API