rs762081862

Variant names:

• chr14-58458545-G-A
• rs762081862
• NM_001329943.3:c.1656G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-58458545-G-A
• chr14-58458545-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001244189.2(KIAA0586):​c.1815G>A​(p.Gln605Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000881 in 1,362,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: KIAA0586 NM_001244189.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.8679
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.54
• 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-58458545-G-A is Pathogenic according to our data. Variant chr14-58458545-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	NM_001329943.3	MANE Select	c.1656G>A	p.Gln552Gln	splice_region synonymous	Exon 12 of 31	NP_001316872.1
	KIAA0586	NM_001244189.2		c.1815G>A	p.Gln605Gln	splice_region synonymous	Exon 14 of 34	NP_001231118.1
	KIAA0586	NM_001329944.2		c.1656G>A	p.Gln552Gln	splice_region synonymous	Exon 12 of 32	NP_001316873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0586	ENST00000652326.2	MANE Select	c.1656G>A	p.Gln552Gln	splice_region synonymous	Exon 12 of 31	ENSP00000498929.1
	KIAA0586	ENST00000619416.4	TSL:1	c.1611G>A	p.Gln537Gln	splice_region synonymous	Exon 13 of 32	ENSP00000478083.1
	KIAA0586	ENST00000423743.7	TSL:1	c.1524G>A	p.Gln508Gln	splice_region synonymous	Exon 13 of 32	ENSP00000399427.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000138 AC: 2 AN: 144934 AF XY: 0.0000131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000476

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000881 AC: 12 AN: 1362244 Hom.: 0 Cov.: 23 AF XY: 0.0000104 AC XY: 7 AN XY: 672654

African (AFR) AF: 0.00 AC: 0 AN: 30332

American (AMR) AF: 0.0000304 AC: 1 AN: 32938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24734

East Asian (EAS) AF: 0.00 AC: 0 AN: 34796

South Asian (SAS) AF: 0.00 AC: 0 AN: 74394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5498

European-Non Finnish (NFE) AF: 0.00000949 AC: 10 AN: 1053688

Other (OTH) AF: 0.0000177 AC: 1 AN: 56602

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Short-rib thoracic dysplasia 14 with polydactyly (2)
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
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		5.5
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 0

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

Other links and lift over

dbSNP: rs762081862; hg19: chr14-58925263;