rs397515484

Variant names:

• chr19-57233458-A-G
• rs397515484
• NM_001015878.2:c.436-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001015878.2(AURKC):​c.436-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AURKC NM_001015878.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.93
• 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), Orphanet, Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16021505 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of -24, new splice context is: gtggcaggcttcacttccAGggt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-57233458-A-G is Pathogenic according to our data. Variant chr19-57233458-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66088.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AURKC	NM_001015878.2	c.436-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6	ENST00000302804.12	NP_001015878.1
AURKC	NM_001015879.2	c.379-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6		NP_001015879.1
AURKC	NM_003160.3	c.334-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6		NP_003151.2
AURKC	XM_047439253.1	c.441-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 4		XP_047295209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AURKC	ENST00000302804.12	c.436-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6	1	NM_001015878.2	ENSP00000302898.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000131 Hom.: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Dec 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		7.9
GERP RS		3.2
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs397515484; hg19: chr19-57744826;