Variant 19-57231759-A-ACAGCCCAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001015878.2(AURKC):c.94_101dupAGCCCAGC(p.Met35AlafsTer40) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

AURKC
NM_001015878.2 frameshift, splice_region

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: -0.176

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-57231759-A-ACAGCCCAG is Pathogenic according to our data. Variant chr19-57231759-A-ACAGCCCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 632323.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AURKC	NM_001015878.2 link	c.94_101dupAGCCCAGC	p.Met35AlafsTer40	frameshift_variant, splice_region_variant	Exon 2 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.94_101dupAGCCCAGC	p.Met35AlafsTer40	frameshift_variant, splice_region_variant	Exon 2 of 7	1	NM_001015878.2	ENSP00000302898.6		Q9UQB9-1

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

151432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000204

AC:

AN:

250472

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

181

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000261

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000152

AC:

AN:

151432

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

73888

show subpopulations

Gnomad4 AFR

AF:

0.0000486

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000482

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Nov 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Met35Alafs*40) in the AURKC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs757923465, ExAC 0.02%). This variant has not been reported in the literature in individuals with AURKC-related disease. Loss-of-function variants in AURKC are known to be pathogenic (PMID: 17435757, 19147683, 22888167). For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Nov 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met35AlafsX40 variant in AURKC has not been previously reported in individ uals with spermatogenic failure, but has been identified in 0.1% (11/10368) of A shkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This v ariant is predicted to cause a frameshift in some (e.g. NM_001015878.1 and NM_00 1015879.1) but not all of the transcripts produced by the gene. It occurs upstre am of the start codon of an alternate transcript (NM_003160.2) and the two known pathogenic loss of function variants in this gene (p.Tyr248X and p.Leu49TrpfsX2 3) occur downstream of the start codon in all 3 transcripts. Loss of AURKC funct ion is an established disease mechanism in individuals with spermatogenic failur e (Dieterich 2007, Ben Khelifa 2011, Ben Khelifa 2012); however, given uncertain ty around which transcripts are biologically relevant, the p.Met35AlafsX40 varia nt is uncertain. ACMG/AMP Criteria applied: None. -

Infertility associated with multi-tailed spermatozoa and excessive DNA

Uncertain:1

Jul 14, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AURKC c.94_101dupAGCCCAGC (p.Met35AlafsTer40) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for spermatogenic failure. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over