22-24433541-T-C

Position:

• chr22-24433541-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000675.6(ADORA2A):​c.137T>C​(p.Val46Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADORA2A NM_000675.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

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]

SPECC1L-ADORA2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4148616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADORA2A	NM_000675.6	c.137T>C	p.Val46Ala	missense_variant	2/3	ENST00000337539.12	NP_000666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADORA2A	ENST00000337539.12	c.137T>C	p.Val46Ala	missense_variant	2/3	1	NM_000675.6	ENSP00000336630.6
SPECC1L-ADORA2A	ENST00000358654.2	n.*1272T>C		non_coding_transcript_exon_variant	19/20	2		ENSP00000351480.2
SPECC1L-ADORA2A	ENST00000358654.2	n.*1272T>C		3_prime_UTR_variant	19/20	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.137T>C (p.V46A) alteration is located in exon 2 (coding exon 1) of the ADORA2A gene. This alteration results from a T to C substitution at nucleotide position 137, causing the valine (V) at amino acid position 46 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	.;D;.;.;.;D;D;D;.;.
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.73	T;T;T;T;T;.;.;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	.;L;.;.;.;L;L;L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.6	D;.;.;D;.;D;.;.;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.071	T;.;.;T;.;T;.;.;T;T
Sift4G	Benign	0.070	T;T;T;T;T;T;T;T;T;T
Polyphen		0.39	.;B;.;.;.;B;B;B;.;.
Vest4		0.14, 0.20, 0.20, 0.20
MutPred		0.71		Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);Gain of glycosylation at S47 (P = 0.2599);
MVP		0.84
MPC		0.76
ClinPred		0.78	D
GERP RS		2.4
Varity_R		0.51
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24829509;