rs148006211

Variant names:

• chr14-58450673-A-G
• rs148006211
• NM_001329943.3:c.1056A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001329943.3(KIAA0586):​c.1056A>G​(p.Ser352Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,609,474 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (2 hom.)
• Consequence: KIAA0586 NM_001329943.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.328
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 14-58450673-A-G is Benign according to our data. Variant chr14-58450673-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.328 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0046 (701/152330) while in subpopulation AFR AF = 0.0161 (671/41574). AF 95% confidence interval is 0.0151. There are 3 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1056A>G	p.Ser352Ser	synonymous	Exon 8 of 31	NP_001316872.1	A0A494C171
	KIAA0586	NM_001244189.2		c.1215A>G	p.Ser405Ser	synonymous	Exon 10 of 34	NP_001231118.1	Q9BVV6-3
	KIAA0586	NM_001329944.2		c.1056A>G	p.Ser352Ser	synonymous	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.1056A>G	p.Ser352Ser	synonymous	Exon 8 of 31	ENSP00000498929.1	A0A494C171
	KIAA0586	ENST00000619416.4	TSL:1	c.1011A>G	p.Ser337Ser	synonymous	Exon 9 of 32	ENSP00000478083.1	Q9BVV6-1
	KIAA0586	ENST00000423743.7	TSL:1	c.924A>G	p.Ser308Ser	synonymous	Exon 9 of 32	ENSP00000399427.3	Q9BVV6-4

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 699 AN: 152212 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00119 AC: 296 AN: 248758 AF XY: 0.000830

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000489 AC: 713 AN: 1457144 Hom.: 2 Cov.: 29 AF XY: 0.000394 AC XY: 286 AN XY: 725204

African (AFR) AF: 0.0178 AC: 593 AN: 33366

American (AMR) AF: 0.00107 AC: 48 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.00000903 AC: 10 AN: 1107852

Other (OTH) AF: 0.000930 AC: 56 AN: 60218

GnomAD4 genome AF: 0.00460 AC: 701 AN: 152330 Hom.: 3 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74506

African (AFR) AF: 0.0161 AC: 671 AN: 41574

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00395 Hom.: 3

Bravo AF: 0.00485

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.3
DANN	Benign	0.67
PhyloP100		0.33
Mutation Taster		=96/4	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: rs148006211; hg19: chr14-58917391;