chr22-24440689-G-A

Position:

chr22-24440689-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000675.6(ADORA2A):c.439G>A(p.Gly147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,613,652 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 56 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 38 hom. )

Consequence

ADORA2A
NM_000675.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.00

Variant links:

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]

ADORA2A links:

SPECC1L-ADORA2A (HGNC:):

SPECC1L-ADORA2A links:

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

ADORA2A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018239319).

BP6

Variant 22-24440689-G-A is Benign according to our data. Variant chr22-24440689-G-A is described in ClinVar as [Benign]. Clinvar id is 769157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2178/152280) while in subpopulation AFR AF= 0.0494 (2051/41552). AF 95% confidence interval is 0.0476. There are 56 homozygotes in gnomad4. There are 1050 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADORA2A	NM_000675.6 linkuse as main transcript	c.439G>A	p.Gly147Ser	missense_variant	3/3	ENST00000337539.12	NP_000666.2
SPECC1L-ADORA2A	NR_103546.1 linkuse as main transcript	n.4618G>A		non_coding_transcript_exon_variant	20/20
ADORA2A-AS1	NR_028484.3 linkuse as main transcript	n.833+1303C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12 linkuse as main transcript	c.439G>A	p.Gly147Ser	missense_variant	3/3	1	NM_000675.6	ENSP00000336630	P1
ADORA2A-AS1	ENST00000326341.8 linkuse as main transcript	n.559+1303C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2174

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00350

AC:

880

AN:

251202

Hom.:

AF XY:

0.00261

AC XY:

354

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00152

AC:

2217

AN:

1461372

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

926

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.0485

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.0143

AC:

2178

AN:

152280

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1050

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0494

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0138

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.0162

ESP6500AA

AF:

0.0427

AC:

188

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00409

AC:

497

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.044

DANN

Benign

0.84

DEOGEN2

Benign

0.14

T;.;T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.018

T;T;.;.;.

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.39

N;.;N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.31

.;N;N;.;.

REVEL

Benign

0.0060

Sift

Benign

1.0

.;T;T;.;.

Sift4G

Benign

0.99

T;T;T;T;T

Polyphen

0.0

B;.;B;B;B

Vest4

0.027

MVP

0.19

MPC

0.53

ClinPred

0.0012

GERP RS

-5.1

Varity_R

0.21

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over