14-58487145-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_001329943.3(KIAA0586):c.3283A>C(p.Lys1095Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,611,814 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 12 hom. )

Consequence

KIAA0586
NM_001329943.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.599

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059957504).

BP6

Variant 14-58487145-A-C is Benign according to our data. Variant chr14-58487145-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 12 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329943.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIAA0586	NM_001329943.3	MANE Select	c.3283A>C	p.Lys1095Gln	missense	Exon 22 of 31	NP_001316872.1
KIAA0586	NM_001244189.2		c.3442A>C	p.Lys1148Gln	missense	Exon 24 of 34	NP_001231118.1
KIAA0586	NM_001329944.2		c.3283A>C	p.Lys1095Gln	missense	Exon 22 of 32	NP_001316873.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIAA0586	ENST00000652326.2	MANE Select	c.3283A>C	p.Lys1095Gln	missense	Exon 22 of 31	ENSP00000498929.1
KIAA0586	ENST00000619416.4	TSL:1	c.3238A>C	p.Lys1080Gln	missense	Exon 23 of 32	ENSP00000478083.1
KIAA0586	ENST00000423743.7	TSL:1	c.3151A>C	p.Lys1051Gln	missense	Exon 23 of 32	ENSP00000399427.3

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

512

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00999

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00202

AC:

496

AN:

246088

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.00958

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000445

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.000926

AC:

1352

AN:

1459512

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

847

AN XY:

725906

show subpopulations

African (AFR)

AF:

0.00914

AC:

305

AN:

33380

American (AMR)

AF:

0.00147

AC:

AN:

44174

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26072

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39684

South Asian (SAS)

AF:

0.00741

AC:

634

AN:

85512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000157

AC:

175

AN:

1111228

Other (OTH)

AF:

0.00164

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00339

AC:

516

AN:

152302

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

266

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0100

AC:

417

AN:

41562

American (AMR)

AF:

0.00170

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00808

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68026

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00982

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.00227

AC:

274

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Joubert syndrome 23 (1)

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)

KIAA0586-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.1

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.028

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.60

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

REVEL

Benign

0.021

Sift

Benign

0.15

Sift4G

Benign

0.17

Polyphen

0.19

Vest4

0.21

MVP

0.23

MPC

0.088

ClinPred

0.012

GERP RS

1.3

Varity_R

0.058

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over