10-111076814-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 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 rank	MANE	Protein	UniProt
ADRA2A	NM_000681.4	c.-1183A>G		upstream_gene_variant		ENST00000280155.4	NP_000672.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA2A	ENST00000280155.4	c.-1183A>G		upstream_gene_variant		6	NM_000681.4	ENSP00000280155.2

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

Gnomad4 AFR AF: 0.00435

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0646

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00250

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0162

Alfa AF: 0.0192 Hom.: 3

Bravo AF: 0.0159

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 13, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.60

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs36022820; hg19: chr10-112836572;