rs1203751352

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001329943.3(KIAA0586):c.789dupA(p.Gln264ThrfsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000373 in 1,609,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KIAA0586
NM_001329943.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.35

Publications

0 publications found

Variant links:

Genes affected

KIAA0586 (HGNC:19960): (KIAA0586) This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Aug 2016]

KIAA0586 Gene-Disease associations (from GenCC):

Joubert syndrome 23
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short-rib thoracic dysplasia 14 with polydactyly
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with Jeune asphyxiating thoracic dystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIAA0586 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 14-58444155-C-CA is Pathogenic according to our data. Variant chr14-58444155-C-CA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 524064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA0586	NM_001329943.3 link	c.789dupA	p.Gln264ThrfsTer11	frameshift_variant	Exon 6 of 31	ENST00000652326.2	NP_001316872.1	A0A494C171

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0586	ENST00000652326.2 link	c.789dupA	p.Gln264ThrfsTer11	frameshift_variant	Exon 6 of 31		NM_001329943.3	ENSP00000498929.1		A0A494C171

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248062

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000874

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457076

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33374

American (AMR)

AF:

0.000112

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

85952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108012

Other (OTH)

AF:

0.00

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Apr 06, 2018

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant that is likely pathogenic has also been identified in the KIAA0586 gene. The c.948dupA variant in the KIAA0586 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.948dupA variant causes a frameshift starting with codon Glutamine 317, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Q317TfsX11. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.948dupA variant is observed in 3/33448 (0.009%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly

Pathogenic:1

Apr 06, 2024

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.Gln317Thrfs*11) in the KIAA0586 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481, 26386044). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. ClinVar contains an entry for this variant (Variation ID: 524064). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.4

Mutation Taster

=0/200

disease causing (ClinVar)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over