19-57231121-C-T

Variant names:

• chr19-57231121-C-T
• rs58264281
• NM_001015878.2:c.-128C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001015878.2(AURKC):​c.-128C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 151,514 control chromosomes in the GnomAD database, including 44,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44871 hom., cov: 29)
  • Exomes 𝑓: 0.83 (464805 hom.)
  • Failed GnomAD Quality Control
• Consequence: AURKC NM_001015878.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00001267
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.12
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-57231121-C-T is Benign according to our data. Variant chr19-57231121-C-T is described in ClinVar as Benign. ClinVar VariationId is 330225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.828 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.-128C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001015878.1	Q9UQB9-1
	AURKC	NM_001015878.2	MANE Select	c.-128C>T		5_prime_UTR	Exon 1 of 7	NP_001015878.1	Q9UQB9-1
	AURKC	NM_001015879.2		c.1+7C>T		splice_region intron	N/A	NP_001015879.1	Q9UQB9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AURKC	ENST00000302804.12	TSL:1 MANE Select	c.-128C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000302898.6	Q9UQB9-1
	AURKC	ENST00000302804.12	TSL:1 MANE Select	c.-128C>T		5_prime_UTR	Exon 1 of 7	ENSP00000302898.6	Q9UQB9-1
	AURKC	ENST00000415300.6	TSL:1	c.1+7C>T		splice_region intron	N/A	ENSP00000407162.1	Q9UQB9-3

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115396 AN: 151398 Hom.: 44862 Cov.: 29

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.906

Gnomad MID AF: 0.736

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.745

GnomAD2 exomes AF: 0.828 AC: 108806 AN: 131394 AF XY: 0.836

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.857

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.925

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.800

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.831 AC: 1100918 AN: 1325072 Hom.: 464805 Cov.: 42 AF XY: 0.833 AC XY: 543735 AN XY: 652370

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

African (AFR) AF: 0.596 AC: 17790 AN: 29848

American (AMR) AF: 0.847 AC: 28680 AN: 33860

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 20633 AN: 23778

East Asian (EAS) AF: 0.841 AC: 29756 AN: 35382

South Asian (SAS) AF: 0.876 AC: 66322 AN: 75718

European-Finnish (FIN) AF: 0.901 AC: 43830 AN: 48672

Middle Eastern (MID) AF: 0.763 AC: 4177 AN: 5474

European-Non Finnish (NFE) AF: 0.830 AC: 844441 AN: 1016900

Other (OTH) AF: 0.817 AC: 45289 AN: 55440

⚠️ 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: 0.762 AC: 115443 AN: 151514 Hom.: 44871 Cov.: 29 AF XY: 0.768 AC XY: 56844 AN XY: 74014

African (AFR) AF: 0.597 AC: 24655 AN: 41302

American (AMR) AF: 0.793 AC: 12099 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2958 AN: 3462

East Asian (EAS) AF: 0.848 AC: 4320 AN: 5092

South Asian (SAS) AF: 0.850 AC: 4086 AN: 4806

European-Finnish (FIN) AF: 0.906 AC: 9554 AN: 10546

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.816 AC: 55254 AN: 67740

Other (OTH) AF: 0.744 AC: 1567 AN: 2106

Alfa AF: 0.787 Hom.: 10254

Bravo AF: 0.748

Asia WGS AF: 0.805 AC: 2796 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Infertility associated with multi-tailed spermatozoa and excessive DNA (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.77
PhyloP100		-1.1
PromoterAI		-0.0066	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.070		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: rs58264281; hg19: chr19-57742489; COSMIC: COSV57139088; COSMIC: COSV57139088;