22-24441135-C-T

Position:

• chr22-24441135-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The ENST00000337539.12(ADORA2A):​c.885C>T​(p.Phe295=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0079 in 1,614,206 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (71 hom.)
• Consequence: ADORA2A ENST00000337539.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.84

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=-0.44).
• BP6: Variant 22-24441135-C-T is Benign according to our data. Variant chr22-24441135-C-T is described in ClinVar as [Benign]. Clinvar id is 774536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 697 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.885C>T	p.Phe295=	synonymous_variant	3/3	ENST00000337539.12	NP_000666.2
SPECC1L-ADORA2A	NR_103546.1	n.5064C>T		non_coding_transcript_exon_variant	20/20
ADORA2A-AS1	NR_028484.3	n.833+857G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.885C>T	p.Phe295=	synonymous_variant	3/3	1	NM_000675.6	ENSP00000336630	P1
ADORA2A-AS1	ENST00000326341.8	n.559+857G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152246 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00434 AC: 1092 AN: 251426 Hom.: 2 AF XY: 0.00421 AC XY: 572 AN XY: 135900

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00733

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00825 AC: 12062 AN: 1461842 Hom.: 71 Cov.: 30 AF XY: 0.00802 AC XY: 5834 AN XY: 727228

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00702

GnomAD4 genome AF: 0.00457 AC: 697 AN: 152364 Hom.: 2 Cov.: 33 AF XY: 0.00464 AC XY: 346 AN XY: 74516

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00791

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00707 Hom.: 5

Bravo AF: 0.00488

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00747

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.7
DANN	Benign	0.92

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: rs17650937; hg19: chr22-24837103; COSMIC: COSV58379508;