rs5751876

Variant names:

• chr22-24441333-T-C
• rs5751876
• NM_000675.6:c.1083T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000675.6(ADORA2A):​c.1083T>C​(p.Tyr361Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,598,650 control chromosomes in the GnomAD database, including 270,079 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 0.52 (21560 hom., cov: 33)
  • Exomes 𝑓: 0.58 (248519 hom.)
• Consequence: ADORA2A NM_000675.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.40
• Publications: 191 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.602 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA2A	NM_000675.6	MANE Select	c.1083T>C	p.Tyr361Tyr	synonymous	Exon 3 of 3	NP_000666.2
	ADORA2A	NM_001278497.2		c.1083T>C	p.Tyr361Tyr	synonymous	Exon 4 of 4	NP_001265426.1	P29274
	ADORA2A	NM_001278498.2		c.1083T>C	p.Tyr361Tyr	synonymous	Exon 3 of 3	NP_001265427.1	X5DNB4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA2A	ENST00000337539.12	TSL:1 MANE Select	c.1083T>C	p.Tyr361Tyr	synonymous	Exon 3 of 3	ENSP00000336630.6	P29274
	ADORA2A	ENST00000618076.3	TSL:1	c.1083T>C	p.Tyr361Tyr	synonymous	Exon 3 of 3	ENSP00000481552.1	P29274
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.*2218T>C		non_coding_transcript_exon	Exon 20 of 20	ENSP00000351480.2	F8WAN1

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78978 AN: 152010 Hom.: 21544 Cov.: 33

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.544 AC: 128346 AN: 235996 AF XY: 0.538

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.584

Gnomad EAS exome AF: 0.503

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.600

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.581 AC: 840705 AN: 1446522 Hom.: 248519 Cov.: 85 AF XY: 0.575 AC XY: 413087 AN XY: 718016

African (AFR) AF: 0.358 AC: 11873 AN: 33202

American (AMR) AF: 0.604 AC: 26197 AN: 43398

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 14813 AN: 25050

East Asian (EAS) AF: 0.501 AC: 19786 AN: 39454

South Asian (SAS) AF: 0.359 AC: 30395 AN: 84624

European-Finnish (FIN) AF: 0.571 AC: 29825 AN: 52202

Middle Eastern (MID) AF: 0.554 AC: 3156 AN: 5692

European-Non Finnish (NFE) AF: 0.608 AC: 671019 AN: 1103288

Other (OTH) AF: 0.564 AC: 33641 AN: 59612

GnomAD4 genome AF: 0.520 AC: 79045 AN: 152128 Hom.: 21560 Cov.: 33 AF XY: 0.516 AC XY: 38372 AN XY: 74356

African (AFR) AF: 0.362 AC: 15021 AN: 41502

American (AMR) AF: 0.561 AC: 8583 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2057 AN: 3472

East Asian (EAS) AF: 0.494 AC: 2549 AN: 5164

South Asian (SAS) AF: 0.348 AC: 1675 AN: 4818

European-Finnish (FIN) AF: 0.572 AC: 6053 AN: 10584

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.607 AC: 41266 AN: 67982

Other (OTH) AF: 0.543 AC: 1147 AN: 2112

Alfa AF: 0.565 Hom.: 9964

Bravo AF: 0.520

Asia WGS AF: 0.411 AC: 1430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.45
PhyloP100		-3.4
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: rs5751876; hg19: chr22-24837301; COSMIC: COSV58379336; COSMIC: COSV58379336;