chr19-57231260-C-G

Position:

• chr19-57231260-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP7 BS1_Supporting BS2

The ENST00000302804.12(AURKC):​c.12C>G​(p.Pro4=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,552,262 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 30)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: AURKC ENST00000302804.12 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.781

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-0.781 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00208 (316/152224) while in subpopulation AFR AF= 0.0072 (299/41534). AF 95% confidence interval is 0.00653. There are 3 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AURKC	NM_001015878.2	c.12C>G	p.Pro4=	synonymous_variant	1/7	ENST00000302804.12	NP_001015878.1
AURKC	XM_047439253.1	c.12C>G	p.Pro4=	synonymous_variant	1/5		XP_047295209.1
AURKC	NM_001015879.2	c.1+146C>G		intron_variant			NP_001015879.1
AURKC	NM_003160.3	c.-45+141C>G		intron_variant			NP_003151.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AURKC	ENST00000302804.12	c.12C>G	p.Pro4=	synonymous_variant	1/7	1	NM_001015878.2	ENSP00000302898	A2
AURKC	ENST00000599062.5	c.12C>G	p.Pro4=	synonymous_variant	1/7	1		ENSP00000469983	P2
AURKC	ENST00000415300.6	c.1+146C>G		intron_variant		1		ENSP00000407162
AURKC	ENST00000601799.5	c.12C>G	p.Pro4=	synonymous_variant, NMD_transcript_variant	1/6	3		ENSP00000468918

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152106 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000508 AC: 79 AN: 155502 Hom.: 0 AF XY: 0.000390 AC XY: 32 AN XY: 82014

Gnomad AFR exome AF: 0.00629

Gnomad AMR exome AF: 0.000562

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000238 AC: 333 AN: 1400038 Hom.: 0 Cov.: 41 AF XY: 0.000222 AC XY: 153 AN XY: 690574

Gnomad4 AFR exome AF: 0.00749

Gnomad4 AMR exome AF: 0.000558

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000222

Gnomad4 OTH exome AF: 0.000379

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152224 Hom.: 3 Cov.: 30 AF XY: 0.00192 AC XY: 143 AN XY: 74440

Gnomad4 AFR AF: 0.00720

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000675 Hom.: 1

Bravo AF: 0.00209

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs73633650; hg19: chr19-57742628;