10-111078579-G-A

Position:

• chr10-111078579-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000681.4(ADRA2A):​c.583G>A​(p.Gly195Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,598,226 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: ADRA2A NM_000681.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074337423).
• BS2: High Homozygotes in GnomAdExome4 at 2 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
ADRA2A	NM_000681.4	c.583G>A	p.Gly195Ser	missense_variant	1/1	ENST00000280155.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRA2A	ENST00000280155.4	c.583G>A	p.Gly195Ser	missense_variant	1/1		NM_000681.4	P1

Frequencies

GnomAD3 genomes AF: 0.000284 AC: 43 AN: 151524 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000379 AC: 84 AN: 221392 Hom.: 1 AF XY: 0.000329 AC XY: 40 AN XY: 121416

Gnomad AFR exome AF: 0.0000784

Gnomad AMR exome AF: 0.000543

Gnomad ASJ exome AF: 0.00336

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000309

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.000249 AC: 360 AN: 1446588 Hom.: 2 Cov.: 31 AF XY: 0.000256 AC XY: 184 AN XY: 718386

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000544

Gnomad4 ASJ exome AF: 0.00289

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000294

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.000637

GnomAD4 genome AF: 0.000284 AC: 43 AN: 151638 Hom.: 0 Cov.: 33 AF XY: 0.000270 AC XY: 20 AN XY: 74146

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000584 AC: 5

ExAC AF: 0.000352 AC: 42

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.583G>A (p.G195S) alteration is located in exon 1 (coding exon 1) of the ADRA2A gene. This alteration results from a G to A substitution at nucleotide position 583, causing the glycine (G) at amino acid position 195 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.64	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.33	T
Vest4		0.28
MVP		0.50
ClinPred		0.013	T
GERP RS		3.2
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200592713; hg19: chr10-112838337; COSMIC: COSV54528144;