14-58428458-C-T

Variant names:

• chr14-58428458-C-T
• rs797045119
• NM_001329943.3:c.194C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001329943.3(KIAA0586):​c.194C>T​(p.Ser65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S65P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0150
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036599636).
• BP6: Variant 14-58428458-C-T is Benign according to our data. Variant chr14-58428458-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3288096.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.194C>T	p.Ser65Leu	missense	Exon 1 of 31	NP_001316872.1
	KIAA0586	NM_001244189.2		c.230C>T	p.Ser77Leu	missense	Exon 2 of 34	NP_001231118.1
	KIAA0586	NM_001329944.2		c.194C>T	p.Ser65Leu	missense	Exon 1 of 32	NP_001316873.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.194C>T	p.Ser65Leu	missense	Exon 1 of 31	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.149C>T	p.Ser50Leu	missense	Exon 2 of 32	ENSP00000478083.1
	KIAA0586	ENST00000261244.9	TSL:1	c.194C>T	p.Ser65Leu	missense	Exon 1 of 30	ENSP00000261244.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455390 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 724428

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44690

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106152

Other (OTH) AF: 0.0000166 AC: 1 AN: 60198

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.5
DANN	Benign	0.92
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.015
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.29		Gain of catalytic residue at S50 (P = 0)
MVP		0.23
MPC		0.019
ClinPred		0.069	T
GERP RS		1.5
PromoterAI		0.14	Neutral
Varity_R		0.027
gMVP		0.038
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797045119; hg19: chr14-58895176;