rs5996696

Variant names:

• chr22-24431654-A-C
• rs5996696
• NM_000675.6:c.-274-1477A>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.-274-1477A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0811 in 380,228 control chromosomes in the GnomAD database, including 3,097 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 0.11 (2217 hom., cov: 32)
  • Exomes 𝑓: 0.059 (880 hom.)
• Consequence: ADORA2A NM_000675.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51
• Publications: 19 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.-274-1477A>C		intron_variant	Intron 1 of 2	ENST00000337539.12	NP_000666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.-274-1477A>C		intron_variant	Intron 1 of 2	1	NM_000675.6	ENSP00000336630.6
SPECC1L-ADORA2A	ENST00000358654.2	n.*862-1477A>C		intron_variant	Intron 18 of 19	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17304 AN: 152034 Hom.: 2207 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0624

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.0896

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0946

GnomAD4 exome AF: 0.0590 AC: 13467 AN: 228076 Hom.: 880 Cov.: 0 AF XY: 0.0647 AC XY: 8202 AN XY: 126844

African (AFR) AF: 0.309 AC: 1941 AN: 6272

American (AMR) AF: 0.0323 AC: 558 AN: 17264

Ashkenazi Jewish (ASJ) AF: 0.0402 AC: 224 AN: 5576

East Asian (EAS) AF: 0.0962 AC: 830 AN: 8628

South Asian (SAS) AF: 0.126 AC: 5910 AN: 46910

European-Finnish (FIN) AF: 0.0236 AC: 223 AN: 9446

Middle Eastern (MID) AF: 0.0309 AC: 27 AN: 874

European-Non Finnish (NFE) AF: 0.0259 AC: 3177 AN: 122428

Other (OTH) AF: 0.0540 AC: 577 AN: 10678

GnomAD4 genome AF: 0.114 AC: 17361 AN: 152152 Hom.: 2217 Cov.: 32 AF XY: 0.114 AC XY: 8450 AN XY: 74394

African (AFR) AF: 0.309 AC: 12820 AN: 41438

American (AMR) AF: 0.0623 AC: 952 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.0906 AC: 469 AN: 5178

South Asian (SAS) AF: 0.149 AC: 720 AN: 4822

European-Finnish (FIN) AF: 0.0251 AC: 266 AN: 10618

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0266 AC: 1807 AN: 68016

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0662 Hom.: 1707

Bravo AF: 0.124

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.43
PhyloP100		-2.5
PromoterAI		0.0079	Neutral
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: rs5996696; hg19: chr22-24827622;