rs5751876

Variant names:

• chr22-24441333-T-C
• rs5751876
• NM_000675.6:c.1083T>C
• ADORA2A p.Tyr361Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -13 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP7

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 cumulative frequency of 0.575 (AC=919,750) in the gnomAD database across 1,598,650 control chromosomes, including 270,079 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.607. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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: 62 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): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6070 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000675.6. You can select a different transcript below to see updated classification 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	Prot: NP_000666.2
	ADORA2A NM_001278497.2		c.1083T>C p.Tyr361Tyr	synonymous	Exon 4 of 4	Prot: NP_001265426.1 UniProt:
	ADORA2A NM_001278498.2		c.1083T>C p.Tyr361Tyr	synonymous	Exon 3 of 3	Prot: NP_001265427.1 UniProt:

ADORA2A NM_000675.6

MANE Select

HGVSc / HGVSpc.1083T>Cp.Tyr361Tyr

Exon rankExon 3 of 3

synonymous

Prot: NP_000666.2

ADORA2A NM_001278497.2

HGVSc / HGVSpc.1083T>Cp.Tyr361Tyr

Exon rankExon 4 of 4

synonymous

Prot: NP_001265426.1UniProt: P29274X5DNB4

ADORA2A NM_001278498.2

HGVSc / HGVSpc.1083T>Cp.Tyr361Tyr

Exon rankExon 3 of 3

synonymous

Prot: NP_001265427.1UniProt: X5DNB4P29274

Ensembl Transcripts

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

ADORA2A ENST00000337539.12

TSL:1MANE Select

HGVSc / HGVSpc.1083T>Cp.Tyr361Tyr

Exon rankExon 3 of 3

synonymous

Prot: ENSP00000336630.6UniProt: P29274

ADORA2A ENST00000618076.3

TSL:1

HGVSc / HGVSpc.1083T>Cp.Tyr361Tyr

Exon rankExon 3 of 3

synonymous

Prot: ENSP00000481552.1UniProt: P29274

SPECC1L-ADORA2A ENST00000358654.2

TSL:2

HGVSc / HGVSpn.*2218T>C

Exon rankExon 20 of 20

3_prime_UTR

Prot: ENSP00000351480.2UniProt: F8WAN1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.520	AC:78978	Hom:21544	AN:152010	Cov:33
GnomAD2 exomes	AF: 0.544	AC:128346	Hom:	AN:235996	Cov:
GnomAD4 exome	AF: 0.581	AC:840705	Hom:248519	AN:1446522	Cov:85
GnomAD4 genome	AF: 0.520	AC:79045	Hom:21560	AN:152128	Cov:33
TOPMed (Bravo)	AF: 0.520	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.559	AC:37529	Hom:10820	AN:67154	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.567	AC:1327	Hom:386	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.507	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.510	AC:153	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.518	AC:6737	Hom:	AN:13004	Cov:
GenomeAsia100K	AF: 0.411	AC:1430	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.554	AC:4005	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.532	AC:1035	Hom:	AN:1944	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.477	AC:58369	Hom:13994	AN:122424	Cov:
Turkish Variome	AF: 0.540	AC:3476	Hom:961	AN:6442	Cov:
UK10K	AF: 0.604	AC:4569	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.496	AC:4441	Hom:1115	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.585 *	5578	9534	0.597 *	6205	10390
BipEx(Bipolar disorder (including schizoaffective))	0.601	17079	28420	0.604	17413	28844
Epi25(Epilepsy)	0.572	23983	41958	0.571	38022	66532
SCHEMA(Schizophrenia)	0.515	78353	152036	0.533	142813	268186

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.15
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.45
GPN-Star LLR	N/A	1.0
GPN-Star score	N/A	-1.0
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-3.4

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.12
Pangolin gain	Benign	0.12	Position offset: 12
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs5751876;

hg19: chr22-24837301;

COSMIC: COSV58379336;

COSMIC: COSV58379336;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar