22-24302045-CAAAAAA-CAAAAAAAA

Variant names:

• chr22-24302045-C-CAA
• rs759458885
• NM_015330.6:c.-37-136_-37-135dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015330.6(SPECC1L):​c.-37-136_-37-135dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 462,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: SPECC1L NM_015330.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 0 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015330.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1L	NM_015330.6	MANE Select	c.-37-136_-37-135dupAA		intron	N/A	NP_056145.5	Q69YQ0-1
	SPECC1L	NM_001145468.4		c.-37-136_-37-135dupAA		intron	N/A	NP_001138940.4	Q69YQ0-1
	SPECC1L	NM_001254732.3		c.-37-136_-37-135dupAA		intron	N/A	NP_001241661.3	Q69YQ0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1L	ENST00000314328.14	TSL:1 MANE Select	c.-37-150_-37-149insAA		intron	N/A	ENSP00000325785.8	Q69YQ0-1
	SPECC1L	ENST00000437398.5	TSL:1	c.-37-150_-37-149insAA		intron	N/A	ENSP00000393363.1	Q69YQ0-1
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.-37-150_-37-149insAA		intron	N/A	ENSP00000351480.2	F8WAN1

Frequencies

GnomAD3 genomes AF: 0.0000156 AC: 2 AN: 128508 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000168

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00169 AC: 566 AN: 334418 Hom.: 0 AF XY: 0.00164 AC XY: 294 AN XY: 179804

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00135 AC: 12 AN: 8870

American (AMR) AF: 0.000926 AC: 13 AN: 14032

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 29 AN: 9406

East Asian (EAS) AF: 0.00197 AC: 37 AN: 18828

South Asian (SAS) AF: 0.000358 AC: 14 AN: 39074

European-Finnish (FIN) AF: 0.00158 AC: 28 AN: 17754

Middle Eastern (MID) AF: 0.000753 AC: 1 AN: 1328

European-Non Finnish (NFE) AF: 0.00190 AC: 393 AN: 207314

Other (OTH) AF: 0.00219 AC: 39 AN: 17812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000156 AC: 2 AN: 128508 Hom.: 0 Cov.: 31 AF XY: 0.0000163 AC XY: 1 AN XY: 61506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 35248

American (AMR) AF: 0.00 AC: 0 AN: 12438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3034

East Asian (EAS) AF: 0.00 AC: 0 AN: 4476

South Asian (SAS) AF: 0.00 AC: 0 AN: 4084

European-Finnish (FIN) AF: 0.000143 AC: 1 AN: 6988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000168 AC: 1 AN: 59446

Other (OTH) AF: 0.00 AC: 0 AN: 1728

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.046

Splicing

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

Other links and lift over

dbSNP: rs759458885; hg19: chr22-24698013;