22-24430704-T-C

Variant names:

• chr22-24430704-T-C
• rs3761422
• NM_000675.6:c.-274-2427T>C

Variant summary

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

The NM_000675.6(ADORA2A):​c.-274-2427T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,192 control chromosomes in the GnomAD database, including 29,674 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 0.62 (29674 hom., cov: 35)
• Consequence: ADORA2A NM_000675.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.554
• Publications: 56 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000675.6. 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
	ADORA2A	NM_000675.6	MANE Select	c.-274-2427T>C		intron	N/A	NP_000666.2
	ADORA2A	NM_001278499.2		c.-274-2427T>C		intron	N/A	NP_001265428.1
	ADORA2A	NM_001278500.2		c.-274-2427T>C		intron	N/A	NP_001265429.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA2A	ENST00000337539.12	TSL:1 MANE Select	c.-274-2427T>C		intron	N/A	ENSP00000336630.6
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.*862-2427T>C		intron	N/A	ENSP00000351480.2
	ADORA2A	ENST00000611543.4	TSL:5	c.-274-2427T>C		intron	N/A	ENSP00000483102.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94566 AN: 152072 Hom.: 29623 Cov.: 35

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.616

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

GnomAD4 genome AF: 0.622 AC: 94685 AN: 152192 Hom.: 29674 Cov.: 35 AF XY: 0.620 AC XY: 46170 AN XY: 74410

African (AFR) AF: 0.670 AC: 27831 AN: 41518

American (AMR) AF: 0.598 AC: 9151 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2064 AN: 3470

East Asian (EAS) AF: 0.582 AC: 3014 AN: 5178

South Asian (SAS) AF: 0.569 AC: 2748 AN: 4826

European-Finnish (FIN) AF: 0.594 AC: 6287 AN: 10592

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41580 AN: 67992

Other (OTH) AF: 0.617 AC: 1301 AN: 2110

Alfa AF: 0.611 Hom.: 56658

Bravo AF: 0.630

Asia WGS AF: 0.565 AC: 1962 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.5
DANN	Benign	0.60
PhyloP100		-0.55
Mutation Taster		=100/0	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: rs3761422; hg19: chr22-24826672;