10-111077315-G-C

Variant names:

• chr10-111077315-G-C
• rs2484516
• NM_000681.4:c.-682G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000681.4(ADRA2A):​c.-682G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 152,792 control chromosomes in the GnomAD database, including 67,733 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.94 (67436 hom., cov: 35)
  • Exomes 𝑓: 0.96 (297 hom.)
• Consequence: ADRA2A NM_000681.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	NM_000681.4	MANE Select	c.-682G>C		5_prime_UTR	Exon 1 of 1	NP_000672.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	ENST00000280155.4	TSL:6 MANE Select	c.-682G>C		5_prime_UTR	Exon 1 of 1	ENSP00000280155.2

Frequencies

GnomAD3 genomes AF: 0.941 AC: 143092 AN: 152024 Hom.: 67392 Cov.: 35

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.941

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.923

Gnomad EAS AF: 0.888

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.943

GnomAD4 exome AF: 0.956 AC: 623 AN: 652 Hom.: 297 Cov.: 0 AF XY: 0.963 AC XY: 422 AN XY: 438

African (AFR) AF: 0.800 AC: 8 AN: 10

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 6 AN: 6

East Asian (EAS) AF: 0.955 AC: 21 AN: 22

South Asian (SAS) AF: 0.990 AC: 101 AN: 102

European-Finnish (FIN) AF: 0.875 AC: 7 AN: 8

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.949 AC: 448 AN: 472

Other (OTH) AF: 1.00 AC: 26 AN: 26

GnomAD4 genome AF: 0.941 AC: 143194 AN: 152140 Hom.: 67436 Cov.: 35 AF XY: 0.942 AC XY: 70057 AN XY: 74388

African (AFR) AF: 0.930 AC: 38634 AN: 41526

American (AMR) AF: 0.961 AC: 14689 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.923 AC: 3203 AN: 3470

East Asian (EAS) AF: 0.889 AC: 4558 AN: 5128

South Asian (SAS) AF: 0.905 AC: 4366 AN: 4824

European-Finnish (FIN) AF: 0.972 AC: 10326 AN: 10626

Middle Eastern (MID) AF: 0.945 AC: 276 AN: 292

European-Non Finnish (NFE) AF: 0.946 AC: 64298 AN: 67972

Other (OTH) AF: 0.940 AC: 1986 AN: 2112

Alfa AF: 0.949 Hom.: 3733

Bravo AF: 0.939

Asia WGS AF: 0.889 AC: 3085 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.2
DANN	Benign	0.87
PhyloP100		-1.0
PromoterAI		0.0010	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2484516; hg19: chr10-112837073;