22-24430704-T-C

Position:

• chr22-24430704-T-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.-274-2427T>C		intron_variant		ENST00000337539.12	NP_000666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.-274-2427T>C		intron_variant		1	NM_000675.6	ENSP00000336630.6
SPECC1L-ADORA2A	ENST00000358654.2	n.*862-2427T>C		intron_variant		2		ENSP00000351480.2

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

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.595

Gnomad4 EAS AF: 0.582

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.612

Gnomad4 OTH AF: 0.617

Alfa AF: 0.610 Hom.: 33131

Bravo AF: 0.630

Asia WGS AF: 0.565 AC: 1962 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.5
DANN	Benign	0.60

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: rs3761422; hg19: chr22-24826672;