10-111078696-A-G

Position:

• chr10-111078696-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000681.4(ADRA2A):​c.700A>G​(p.Ile234Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ADRA2A NM_000681.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRA2A	NM_000681.4	c.700A>G	p.Ile234Val	missense_variant	1/1	ENST00000280155.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRA2A	ENST00000280155.4	c.700A>G	p.Ile234Val	missense_variant	1/1		NM_000681.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399578 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

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

Mar 11, 2022

The c.700A>G (p.I234V) alteration is located in exon 1 (coding exon 1) of the ADRA2A gene. This alteration results from a A to G substitution at nucleotide position 700, causing the isoleucine (I) at amino acid position 234 to be replaced by a valine (V). 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.52
MVP		0.48
ClinPred		0.98	D
GERP RS		4.0
gMVP		0.80

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: rs762958713; hg19: chr10-112838454;