chr22-24434627-T-C

Variant names:

• chr22-24434627-T-C
• rs2267076
• NM_000675.6:c.332+891T>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.332+891T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,056 control chromosomes in the GnomAD database, including 31,668 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 0.64 (31668 hom., cov: 32)
• Consequence: ADORA2A NM_000675.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 30 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.332+891T>C		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.332+891T>C		intron_variant	Intron 2 of 2	1	NM_000675.6	ENSP00000336630.6
SPECC1L-ADORA2A	ENST00000358654.2	n.*1467+891T>C		intron_variant	Intron 19 of 19	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97658 AN: 151938 Hom.: 31617 Cov.: 32

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.643 AC: 97774 AN: 152056 Hom.: 31668 Cov.: 32 AF XY: 0.638 AC XY: 47413 AN XY: 74304

African (AFR) AF: 0.689 AC: 28592 AN: 41508

American (AMR) AF: 0.616 AC: 9414 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 2209 AN: 3468

East Asian (EAS) AF: 0.581 AC: 3000 AN: 5164

South Asian (SAS) AF: 0.481 AC: 2310 AN: 4806

European-Finnish (FIN) AF: 0.603 AC: 6380 AN: 10572

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43768 AN: 67950

Other (OTH) AF: 0.653 AC: 1377 AN: 2110

Alfa AF: 0.642 Hom.: 58814

Bravo AF: 0.654

Asia WGS AF: 0.527 AC: 1834 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		-1.1
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: rs2267076; hg19: chr22-24830595;