rs11704959

Positions:

• chr22-24424515-C-A
• chr22-24424515-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001278500.2(ADORA2A):​c.-275+887C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0722 in 152,308 control chromosomes in the GnomAD database, including 484 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 0.072 (483 hom., cov: 32)
  • Exomes 𝑓: 0.079 (1 hom.)
• Consequence: ADORA2A NM_001278500.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105

Genes affected

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 (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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA2A	NM_001278500.2	c.-275+887C>A		intron_variant			NP_001265429.1
SPECC1L-ADORA2A	NR_103546.1	n.3906-8616C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPECC1L-ADORA2A	ENST00000358654.2	n.*862-8616C>A		intron_variant		2		ENSP00000351480.2

Frequencies

GnomAD3 genomes AF: 0.0722 AC: 10980 AN: 152050 Hom.: 483 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0799

Gnomad EAS AF: 0.0534

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0813

Gnomad OTH AF: 0.0844

GnomAD4 exome AF: 0.0786 AC: 11 AN: 140 Hom.: 1 Cov.: 0 AF XY: 0.106 AC XY: 10 AN XY: 94

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.0472

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0722 AC: 10981 AN: 152168 Hom.: 483 Cov.: 32 AF XY: 0.0722 AC XY: 5369 AN XY: 74406

Gnomad4 AFR AF: 0.0412

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0799

Gnomad4 EAS AF: 0.0533

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0813

Gnomad4 OTH AF: 0.0830

Alfa AF: 0.0311 Hom.: 15

Bravo AF: 0.0764

Asia WGS AF: 0.0970 AC: 336 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.5
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs11704959; hg19: chr22-24820483;