rs5751876

Positions:

• chr22-24441333-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The ENST00000337539.12(ADORA2A):​c.1083T>C​(p.Tyr361=) 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. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.52 (21560 hom., cov: 33)
  • Exomes 𝑓: 0.58 (248519 hom.)
• Consequence: ADORA2A ENST00000337539.12 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.40

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:):

ADORA2A-AS1 (HGNC:37122): (ADORA2A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 22-24441333-T-C is Benign according to our data. Variant chr22-24441333-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.1083T>C	p.Tyr361=	synonymous_variant	3/3	ENST00000337539.12	NP_000666.2
SPECC1L-ADORA2A	NR_103546.1	n.5262T>C		non_coding_transcript_exon_variant	20/20
ADORA2A-AS1	NR_028484.3	n.833+659A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.1083T>C	p.Tyr361=	synonymous_variant	3/3	1	NM_000675.6	ENSP00000336630	P1
ADORA2A-AS1	ENST00000326341.8	n.559+659A>G		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.544 AC: 128346 AN: 235996 Hom.: 35941 AF XY: 0.538 AC XY: 68845 AN XY: 127944

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 SAS exome AF: 0.355

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

Gnomad4 AFR exome AF: 0.358

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.591

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.571

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.564

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

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.592

Gnomad4 EAS AF: 0.494

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.572

Gnomad4 NFE AF: 0.607

Gnomad4 OTH AF: 0.543

Alfa AF: 0.578 Hom.: 5974

Bravo AF: 0.520

Asia WGS AF: 0.411 AC: 1430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.45

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: rs5751876; hg19: chr22-24837301; COSMIC: COSV58379336; COSMIC: COSV58379336;