rs36022820

Variant names:

• chr10-111076814-A-G
• rs36022820
• NM_000681.4:c.-1183A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-111076814-A-G
• chr10-111076814-A-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BS1 BS2_Supporting

The NM_000681.4(ADRA2A):​c.-1183A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 151,744 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.017 (45 hom., cov: 33)
• Consequence: ADRA2A NM_000681.4 upstream_gene
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.108
• Publications: 4 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-111076814-A-G is Benign according to our data. Variant chr10-111076814-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1316601.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2533/151744) while in subpopulation NFE AF = 0.0237 (1608/67846). AF 95% confidence interval is 0.0227. There are 45 homozygotes in GnomAd4. There are 1184 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2533 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.-1183A>G		upstream_gene	N/A	NP_000672.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	ENST00000280155.4	TSL:6 MANE Select	c.-1183A>G		upstream_gene	N/A	ENSP00000280155.2	P08913

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2535 AN: 151628 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.00436

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0167 AC: 2533 AN: 151744 Hom.: 45 Cov.: 33 AF XY: 0.0160 AC XY: 1184 AN XY: 74138

African (AFR) AF: 0.00435 AC: 180 AN: 41374

American (AMR) AF: 0.0139 AC: 213 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3468

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5112

South Asian (SAS) AF: 0.00250 AC: 12 AN: 4802

European-Finnish (FIN) AF: 0.0237 AC: 250 AN: 10558

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0237 AC: 1608 AN: 67846

Other (OTH) AF: 0.0162 AC: 34 AN: 2100

Alfa AF: 0.0192 Hom.: 3

Bravo AF: 0.0159

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.60
PhyloP100		0.11
PromoterAI		-0.064	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs36022820; hg19: chr10-112836572;