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), Orphanet, Laboratory for Molecular Medicine, Ambry Genetics

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AURKC	NM_001015878.2	c.-128C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000302804.12	NP_001015878.1
AURKC	NM_001015878.2	c.-128C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000302804.12	NP_001015878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AURKC	ENST00000302804.12	c.-128C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_001015878.2	ENSP00000302898.6
AURKC	ENST00000302804.12	c.-128C>T		5_prime_UTR_variant	Exon 1 of 7	1	NM_001015878.2	ENSP00000302898.6

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 = 0.000000), 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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 1655/2178=75.9% -

Infertility associated with multi-tailed spermatozoa and excessive DNA Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;