rs1800035

chr10-111078794-C-Gchr10-111078794-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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. 12/17 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.608

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 Benign. Variant got -12 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRA2A	NM_000681.4	c.798C>G	p.Asn266Lys	missense_variant	1/1	ENST00000280155.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRA2A	ENST00000280155.4	c.798C>G	p.Asn266Lys	missense_variant	1/1		NM_000681.4	P1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1541 AN: 150388 Hom.: 26 Cov.: 33

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

GnomAD3 exomes AF: 0.00194 AC: 30 AN: 15456 Hom.: 0 AF XY: 0.00187 AC XY: 15 AN XY: 8042

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 SAS 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.: 19 Cov.: 31 AF XY: 0.000849 AC XY: 490 AN XY: 577486

Gnomad4 AFR exome AF: 0.0383

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.000450

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000661

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.0102 AC: 1542 AN: 150498 Hom.: 26 Cov.: 33 AF XY: 0.00979 AC XY: 720 AN XY: 73550

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000593

Gnomad4 OTH AF: 0.00623

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.0123

ExAC AF: 0.00161 AC: 36

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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.0
Dann	Benign	0.77
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.19	N
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.013	P
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.19
Sift	Benign	0.30	T
Sift4G	Benign	0.31	T
Vest4		0.29
MVP		0.46
ClinPred		0.020	T
GERP RS		0.90
gMVP		0.33

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

Other links and lift over

dbSNP: rs1800035; hg19: chr10-112838552;