19-57231146-G-GC

Variant names:

• chr19-57231146-G-GC
• rs74179426
• NM_001015878.2:c.-99dupC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001015878.2(AURKC):​c.-99dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,488,986 control chromosomes in the GnomAD database, including 196,064 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.46 (16849 hom., cov: 0)
  • Exomes 𝑓: 0.50 (179215 hom.)
• Consequence: AURKC NM_001015878.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0610
• Publications: 6 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 19-57231146-G-GC is Benign according to our data. Variant chr19-57231146-G-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330226.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

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.-99dupC		5_prime_UTR	Exon 1 of 7	NP_001015878.1	Q9UQB9-1
	AURKC	NM_001015879.2		c.1+36dupC		intron	N/A	NP_001015879.1	Q9UQB9-3
	AURKC	NM_003160.3		c.-45+31dupC		intron	N/A	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.-99dupC		5_prime_UTR	Exon 1 of 7	ENSP00000302898.6	Q9UQB9-1
	AURKC	ENST00000415300.6	TSL:1	c.1+36dupC		intron	N/A	ENSP00000407162.1	Q9UQB9-3
	AURKC	ENST00000923144.1		c.-99dupC		5_prime_UTR	Exon 1 of 7	ENSP00000593203.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69547 AN: 151246 Hom.: 16846 Cov.: 0

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.454

GnomAD2 exomes AF: 0.373 AC: 46709 AN: 125078 AF XY: 0.385

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.0787

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.502 AC: 671249 AN: 1337622 Hom.: 179215 Cov.: 40 AF XY: 0.503 AC XY: 331967 AN XY: 659638

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

African (AFR) AF: 0.340 AC: 10231 AN: 30124

American (AMR) AF: 0.427 AC: 14805 AN: 34632

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 13182 AN: 24238

East Asian (EAS) AF: 0.151 AC: 5390 AN: 35588

South Asian (SAS) AF: 0.505 AC: 38835 AN: 76888

European-Finnish (FIN) AF: 0.548 AC: 26773 AN: 48862

Middle Eastern (MID) AF: 0.485 AC: 2674 AN: 5512

European-Non Finnish (NFE) AF: 0.519 AC: 532772 AN: 1025892

Other (OTH) AF: 0.476 AC: 26587 AN: 55886

⚠️ 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: 0.460 AC: 69567 AN: 151364 Hom.: 16849 Cov.: 0 AF XY: 0.459 AC XY: 33953 AN XY: 73914

African (AFR) AF: 0.353 AC: 14567 AN: 41278

American (AMR) AF: 0.446 AC: 6795 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1874 AN: 3458

East Asian (EAS) AF: 0.165 AC: 834 AN: 5054

South Asian (SAS) AF: 0.483 AC: 2313 AN: 4792

European-Finnish (FIN) AF: 0.542 AC: 5676 AN: 10478

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.528 AC: 35818 AN: 67780

Other (OTH) AF: 0.456 AC: 958 AN: 2102

Alfa AF: 0.145 Hom.: 606

Asia WGS AF: 0.339 AC: 1176 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Spermatogenic Failure (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.061
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74179426; hg19: chr19-57742514; COSMIC: COSV57139517; COSMIC: COSV57139517;