22-24417873-C-T

Variant names:

• chr22-24417873-C-T
• rs5760405
• ENST00000358654.2:n.*861+3129C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000358654.2(SPECC1L-ADORA2A):​n.*861+3129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 151,530 control chromosomes in the GnomAD database, including 2,668 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 0.17 (2664 hom., cov: 32)
  • Exomes 𝑓: 0.22 (4 hom.)
• Consequence: SPECC1L-ADORA2A ENST00000358654.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.862
• Publications: 8 publications found

Genes affected

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 (HGNC:29022): (sperm antigen with calponin homology and coiled-coil domains 1 like) This gene encodes a coiled-coil domain containing protein. The encoded protein may play a critical role in actin-cytoskeletal reorganization during facial morphogenesis. Mutations in this gene are a cause of oblique facial clefting-1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A read-through transcript composed of SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and the downstream ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPECC1L	NM_015330.6	c.*3250C>T		downstream_gene_variant		ENST00000314328.14	NP_056145.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPECC1L-ADORA2A	ENST00000358654.2	n.*861+3129C>T		intron_variant	Intron 18 of 19	2		ENSP00000351480.2
SPECC1L	ENST00000314328.14	c.*3250C>T		downstream_gene_variant		1	NM_015330.6	ENSP00000325785.8
SPECC1L	ENST00000437398.5	c.*3250C>T		downstream_gene_variant		1		ENSP00000393363.1
ADORA2A	ENST00000467385.5	n.-6C>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25557 AN: 151300 Hom.: 2660 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.222 AC: 28 AN: 126 Hom.: 4 Cov.: 0 AF XY: 0.245 AC XY: 24 AN XY: 98

African (AFR) AF: 0.167 AC: 1 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 2 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.229 AC: 22 AN: 96

Other (OTH) AF: 0.200 AC: 2 AN: 10

GnomAD4 genome AF: 0.169 AC: 25562 AN: 151404 Hom.: 2664 Cov.: 32 AF XY: 0.171 AC XY: 12671 AN XY: 73960

African (AFR) AF: 0.0408 AC: 1676 AN: 41090

American (AMR) AF: 0.235 AC: 3575 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 707 AN: 3468

East Asian (EAS) AF: 0.233 AC: 1201 AN: 5152

South Asian (SAS) AF: 0.122 AC: 588 AN: 4816

European-Finnish (FIN) AF: 0.234 AC: 2439 AN: 10428

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14716 AN: 67898

Other (OTH) AF: 0.188 AC: 397 AN: 2108

Alfa AF: 0.112 Hom.: 417

Bravo AF: 0.167

Asia WGS AF: 0.148 AC: 513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.43
DANN	Benign	0.27
PhyloP100		-0.86

Splicing

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

Other links and lift over

dbSNP: rs5760405; hg19: chr22-24813841;