19-57231759-ACAGCCCAG-ACAGCCCAGCAGCCCAGCAGCCCAG

Variant names:

• chr19-57231759-A-ACAGCCCAGCAGCCCAG
• rs749123022
• NM_001015878.2:c.86_101dupAGCCCAGCAGCCCAGC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001015878.2(AURKC):​c.86_101dupAGCCCAGCAGCCCAGC​(p.Met35AlafsTer13) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AURKC NM_001015878.2 frameshift, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.176
• Publications: 0 publications found

Genes affected

AURKC (HGNC:11391): (aurora kinase C) This gene encodes a member of the Aurora subfamily of serine/threonine protein kinases. The encoded protein is a chromosomal passenger protein that forms complexes with Aurora-B and inner centromere proteins and may play a role in organizing microtubules in relation to centrosome/spindle function during mitosis. This gene is overexpressed in several cancer cell lines, suggesting an involvement in oncogenic signal transduction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

AURKC Gene-Disease associations (from GenCC):

• spermatogenic failure 5

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015878.2. 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
	AURKC	NM_001015878.2	MANE Select	c.86_101dupAGCCCAGCAGCCCAGC	p.Met35AlafsTer13	frameshift splice_region	Exon 2 of 7	NP_001015878.1	Q9UQB9-1
	AURKC	NM_001015879.2		c.29_44dupAGCCCAGCAGCCCAGC	p.Met16AlafsTer13	frameshift splice_region	Exon 2 of 7	NP_001015879.1	Q9UQB9-3
	AURKC	NM_003160.3		c.-17_-2dupAGCCCAGCAGCCCAGC		splice_region	Exon 2 of 7	NP_003151.2	Q9UQB9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AURKC	ENST00000302804.12	TSL:1 MANE Select	c.86_101dupAGCCCAGCAGCCCAGC	p.Met35AlafsTer13	frameshift splice_region	Exon 2 of 7	ENSP00000302898.6	Q9UQB9-1
	AURKC	ENST00000599062.5	TSL:1	c.77_92dupAGCCCAGCAGCCCAGC	p.Met32AlafsTer13	frameshift splice_region	Exon 2 of 7	ENSP00000469983.1	Q5Y191
	AURKC	ENST00000415300.6	TSL:1	c.29_44dupAGCCCAGCAGCCCAGC	p.Met16AlafsTer13	frameshift splice_region	Exon 2 of 7	ENSP00000407162.1	Q9UQB9-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727248

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18

Splicing

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

Other links and lift over

dbSNP: rs749123022; hg19: chr19-57743127;