rs200094677

Variant names:

• chr14-58450697-G-C
• rs200094677
• NM_001329943.3:c.1080G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-58450697-G-C
• chr14-58450697-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001329943.3(KIAA0586):​c.1080G>C​(p.Arg360Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,609,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.647
• Publications: 3 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07203132).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.1080G>C	p.Arg360Ser	missense	Exon 8 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.1239G>C	p.Arg413Ser	missense	Exon 10 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.1080G>C	p.Arg360Ser	missense	Exon 8 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.1080G>C	p.Arg360Ser	missense	Exon 8 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.1035G>C	p.Arg345Ser	missense	Exon 9 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.948G>C	p.Arg316Ser	missense	Exon 9 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000887 AC: 22 AN: 247888 AF XY: 0.0000595

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1456962 Hom.: 0 Cov.: 29 AF XY: 0.000119 AC XY: 86 AN XY: 725042

African (AFR) AF: 0.0000300 AC: 1 AN: 33374

American (AMR) AF: 0.000179 AC: 8 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000144 AC: 159 AN: 1107774

Other (OTH) AF: 0.0000997 AC: 6 AN: 60202

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152044 Hom.: 0 Cov.: 33 AF XY: 0.0000943 AC XY: 7 AN XY: 74270

African (AFR) AF: 0.0000242 AC: 1 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Joubert syndrome 23 (1)
-	1	-	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.65
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.023
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		0.38	B
Vest4		0.17
MutPred		0.24		Loss of helix (P = 0.0167)
MVP		0.47
MPC		0.11
ClinPred		0.060	T
GERP RS		1.6
Varity_R		0.22
gMVP		0.31
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs200094677; hg19: chr14-58917415;