dbSNP rs45568037: KIAA0586:p.Pro1520Pro (chr14-58547845-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001244189.2(KIAA0586):c.4804G>A(p.Val1602Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,662 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1602V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 25 hom., cov: 32)

Exomes 𝑓: 0.013 ( 179 hom. )

Consequence

KIAA0586
NM_001244189.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.386

Publications

8 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), G2P, Ambry Genetics
short-rib thoracic dysplasia 14 with polydactyly
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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:

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new If you want to explore the variant's impact on the transcript NM_001244189.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026349127).

BP6

Variant 14-58547845-G-A is Benign according to our data. Variant chr14-58547845-G-A is described in ClinVar as Benign. ClinVar VariationId is 475454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1843/152230) while in subpopulation NFE AF = 0.02 (1360/68006). AF 95% confidence interval is 0.0191. There are 25 homozygotes in GnomAd4. There are 864 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244189.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0586	NM_001329943.3	MANE Select	c.4560G>A	p.Pro1520Pro	synonymous	Exon 31 of 31	NP_001316872.1	A0A494C171
KIAA0586	NM_001244189.2		c.4804G>A	p.Val1602Ile	missense	Exon 34 of 34	NP_001231118.1	Q9BVV6-3
KIAA0586	NM_001329944.2		c.4645G>A	p.Val1549Ile	missense	Exon 32 of 32	NP_001316873.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0586	ENST00000652326.2	MANE Select	c.4560G>A	p.Pro1520Pro	synonymous	Exon 31 of 31	ENSP00000498929.1	A0A494C171
KIAA0586	ENST00000619416.4	TSL:1	c.4515G>A	p.Pro1505Pro	synonymous	Exon 32 of 32	ENSP00000478083.1	Q9BVV6-1
KIAA0586	ENST00000423743.7	TSL:1	c.4428G>A	p.Pro1476Pro	synonymous	Exon 32 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1844

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.0253

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0200

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.0108

AC:

2674

AN:

248598

AF XY:

0.0108

show subpopulations

Gnomad AFR exome

AF:

0.00200

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0163

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0130

AC:

19003

AN:

1461432

Hom.:

179

Cov.:

AF XY:

0.0131

AC XY:

9530

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33472

American (AMR)

AF:

0.00311

AC:

139

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

621

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00326

AC:

281

AN:

86246

European-Finnish (FIN)

AF:

0.0180

AC:

959

AN:

53400

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0146

AC:

16213

AN:

1111652

Other (OTH)

AF:

0.0118

AC:

710

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

922

1844

2767

3689

4611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.0121

AC:

1843

AN:

152230

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

864

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41528

American (AMR)

AF:

0.00635

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00332

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0169

AC:

179

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0200

AC:

1360

AN:

68006

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0163

Hom.:

Bravo

AF:

0.00936

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.6

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

PhyloP100

-0.39

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.040

REVEL

Benign

0.061

Sift

Pathogenic

0.0

gMVP

0.0089

Mutation Taster

=99/1

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over