19-57231104-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001015878.2(AURKC):c.-145G>C 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 0.843 in 1,454,604 control chromosomes in the GnomAD database, including 524,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56277 hom., cov: 31)

Exomes 𝑓: 0.84 ( 467816 hom. )

Consequence

AURKC
NM_001015878.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.22

Publications

15 publications found

Variant links:

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

AURKC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BP6

Variant 19-57231104-G-C is Benign according to our data. Variant chr19-57231104-G-C is described in ClinVar as [Benign]. Clinvar id is 330224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AURKC	NM_001015878.2 link	c.-145G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000302804.12	NP_001015878.1	Q9UQB9-1
AURKC	NM_001015878.2 link	c.-145G>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000302804.12	NP_001015878.1	Q9UQB9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AURKC	ENST00000302804.12 link	c.-145G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_001015878.2	ENSP00000302898.6		Q9UQB9-1
AURKC	ENST00000302804.12 link	c.-145G>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_001015878.2	ENSP00000302898.6		Q9UQB9-1

Frequencies

GnomAD3 genomes

AF:

0.858

AC:

130435

AN:

151952

Hom.:

56225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.928

Gnomad AMI

AF:

0.805

Gnomad AMR

AF:

0.835

Gnomad ASJ

AF:

0.855

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.856

Gnomad FIN

AF:

0.906

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.817

Gnomad OTH

AF:

0.813

GnomAD2 exomes

AF:

0.870

AC:

114415

AN:

131524

AF XY:

0.871

show subpopulations

Gnomad AFR exome

AF:

0.934

Gnomad AMR exome

AF:

0.876

Gnomad ASJ exome

AF:

0.879

Gnomad EAS exome

AF:

0.855

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.834

Gnomad OTH exome

AF:

0.829

GnomAD4 exome

AF:

0.841

AC:

1095440

AN:

1302534

Hom.:

467816

Cov.:

AF XY:

0.842

AC XY:

541445

AN XY:

642976

show subpopulations

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

African (AFR)

AF:

0.940

AC:

29101

AN:

30962

American (AMR)

AF:

0.865

AC:

29678

AN:

34316

Ashkenazi Jewish (ASJ)

AF:

0.866

AC:

20575

AN:

23768

East Asian (EAS)

AF:

0.841

AC:

29759

AN:

35394

South Asian (SAS)

AF:

0.875

AC:

66169

AN:

75650

European-Finnish (FIN)

AF:

0.900

AC:

43854

AN:

48748

Middle Eastern (MID)

AF:

0.780

AC:

4252

AN:

5448

European-Non Finnish (NFE)

AF:

0.831

AC:

825878

AN:

993322

Other (OTH)

AF:

0.841

AC:

46174

AN:

54926

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.331

Heterozygous variant carriers

8319

16638

24956

33275

41594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.858

AC:

130543

AN:

152070

Hom.:

56277

Cov.:

AF XY:

0.861

AC XY:

63964

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.928

AC:

38542

AN:

41520

American (AMR)

AF:

0.835

AC:

12761

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.855

AC:

2966

AN:

3470

East Asian (EAS)

AF:

0.849

AC:

4359

AN:

5134

South Asian (SAS)

AF:

0.853

AC:

4112

AN:

4820

European-Finnish (FIN)

AF:

0.906

AC:

9597

AN:

10588

Middle Eastern (MID)

AF:

0.803

AC:

236

AN:

294

European-Non Finnish (NFE)

AF:

0.817

AC:

55528

AN:

67942

Other (OTH)

AF:

0.811

AC:

1713

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

896

1792

2689

3585

4481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.792

Hom.:

5966

Bravo

AF:

0.859

Asia WGS

AF:

0.829

AC:

2878

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.99

CADD

Benign

0.15

(source)

DANN

Benign

0.43

PhyloP100

-2.2

PromoterAI

-0.060

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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19-57231104-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over