chr14-58487027-GC-AG

Variant names:

• chr14-58487027-GC-AG
• rs386777947
• NM_001329943.3:c.3165_3166delGCinsAG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001329943.3(KIAA0586):​c.3165_3166delGCinsAG​(p.Pro1056Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. L1055L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIAA0586 NM_001329943.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.522
• Publications: 4 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 -2 ACMG points.

• BP6: Variant 14-58487027-GC-AG is Benign according to our data. Variant chr14-58487027-GC-AG is described in ClinVar as Benign. ClinVar VariationId is 475448.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.3165_3166delGCinsAG	p.Pro1056Ala	missense	N/A	NP_001316872.1
	KIAA0586	NM_001244189.2		c.3324_3325delGCinsAG	p.Pro1109Ala	missense	N/A	NP_001231118.1
	KIAA0586	NM_001329944.2		c.3165_3166delGCinsAG	p.Pro1056Ala	missense	N/A	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.3165_3166delGCinsAG	p.Pro1056Ala	missense	N/A	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.3120_3121delGCinsAG	p.Pro1041Ala	missense	N/A	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.3033_3034delGCinsAG	p.Pro1012Ala	missense	N/A	ENSP00000399427.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386777947; hg19: chr14-58953745;