15-69415990-C-CCA

Variant names:

• chr15-69415990-C-CCA
• NM_001367805.3:c.12-3_12-2dupCA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001367805.3(KIF23):​c.12-3_12-2dupCA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KIF23 NM_001367805.3 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• Publications: 0 publications found

Genes affected

KIF23 (HGNC:6392): (kinesin family member 23) The protein encoded by this gene is a member of kinesin-like protein family. This family includes microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. This protein has been shown to cross-bridge antiparallel microtubules and drive microtubule movement in vitro. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

KIF23-AS1 (HGNC:27075): (KIF23 and PAQR5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023931624 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 0 (no position change), new splice context is: tttttaatctatgaccacAGgag. 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367805.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF23	NM_001367805.3	MANE Select	c.12-3_12-2dupCA		splice_acceptor intron	N/A	NP_001354734.1	A0A7I2V5Y5
	KIF23	NM_138555.4		c.12-3_12-2dupCA		splice_acceptor intron	N/A	NP_612565.1	Q02241-1
	KIF23	NM_001367804.2		c.12-3_12-2dupCA		splice_acceptor intron	N/A	NP_001354733.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF23	ENST00000679126.1	MANE Select	c.12-4_12-3insCA		splice_region intron	N/A	ENSP00000504770.1	A0A7I2V5Y5
	KIF23	ENST00000260363.9	TSL:1	c.12-4_12-3insCA		splice_region intron	N/A	ENSP00000260363.4	Q02241-1
	KIF23	ENST00000352331.8	TSL:1	c.12-4_12-3insCA		splice_region intron	N/A	ENSP00000304978.6	Q02241-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416078 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 703812

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

African (AFR) AF: 0.00 AC: 0 AN: 30366

American (AMR) AF: 0.00 AC: 0 AN: 32466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24784

East Asian (EAS) AF: 0.00 AC: 0 AN: 38146

South Asian (SAS) AF: 0.00 AC: 0 AN: 76344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096784

Other (OTH) AF: 0.00 AC: 0 AN: 58574

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

Splicing

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

Other links and lift over

hg19: chr15-69708329;