22-24437792-T-G

Variant names:

• chr22-24437792-T-G
• rs4822489
• NM_000675.6:c.333-2791T>G

Variant summary

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

The NM_000675.6(ADORA2A):​c.333-2791T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 152,212 control chromosomes in the GnomAD database, including 18,869 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 0.48 (18869 hom., cov: 34)
• Consequence: ADORA2A NM_000675.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.137
• Publications: 21 publications found

Genes affected

ADORA2A (HGNC:263): (adenosine A2a receptor) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) superfamily, which is subdivided into classes and subtypes. The receptors are seven-pass transmembrane proteins that respond to extracellular cues and activate intracellular signal transduction pathways. This protein, an adenosine receptor of A2A subtype, uses adenosine as the preferred endogenous agonist and preferentially interacts with the G(s) and G(olf) family of G proteins to increase intracellular cAMP levels. It plays an important role in many biological functions, such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders. Alternative splicing results in multiple transcript variants. A read-through transcript composed of the upstream SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

SPECC1L-ADORA2A (HGNC:49185): (SPECC1L-ADORA2A readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) genes on chromosome 22. The readthrough transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Jun 2013]

ADORA2A-AS1 (HGNC:37122): (ADORA2A antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.333-2791T>G		intron_variant	Intron 2 of 2	ENST00000337539.12	NP_000666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.333-2791T>G		intron_variant	Intron 2 of 2	1	NM_000675.6	ENSP00000336630.6
SPECC1L-ADORA2A	ENST00000358654.2	n.*1468-2791T>G		intron_variant	Intron 19 of 19	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72728 AN: 152094 Hom.: 18859 Cov.: 34

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.508

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

GnomAD4 genome AF: 0.478 AC: 72765 AN: 152212 Hom.: 18869 Cov.: 34 AF XY: 0.475 AC XY: 35371 AN XY: 74406

African (AFR) AF: 0.276 AC: 11468 AN: 41532

American (AMR) AF: 0.527 AC: 8062 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1946 AN: 3470

East Asian (EAS) AF: 0.490 AC: 2537 AN: 5174

South Asian (SAS) AF: 0.320 AC: 1543 AN: 4826

European-Finnish (FIN) AF: 0.549 AC: 5822 AN: 10606

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39630 AN: 67996

Other (OTH) AF: 0.508 AC: 1074 AN: 2114

Alfa AF: 0.519 Hom.: 9556

Bravo AF: 0.477

Asia WGS AF: 0.393 AC: 1366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.2
DANN	Benign	0.65
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4822489; hg19: chr22-24833760;