rs587777376

Variant names:

• chr20-21126167-G-T
• rs587777376
• NM_018474.6:c.52G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-21126167-G-T
• chr20-21126167-G-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_018474.6(KIZ):​c.52G>T​(p.Glu18*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,508,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: KIZ NM_018474.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.00
• Publications: 3 publications found

Genes affected

KIZ (HGNC:15865): (kizuna centrosomal protein) The protein encoded by this gene localizes to centrosomes, strengthening and stabilizing the pericentriolar region prior to spindle formation. The encoded protein usually remains with the mother centrosome after centrosomal duplication. Sevral transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

KIZ Gene-Disease associations (from GenCC):

• KIZ-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 69

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 36 pathogenic variants in the truncated region.
• PP5: Variant 20-21126167-G-T is Pathogenic according to our data. Variant chr20-21126167-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018474.6. 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
	KIZ	NM_018474.6	MANE Select	c.52G>T	p.Glu18*	stop_gained	Exon 1 of 13	NP_060944.3
	KIZ	NM_001352434.2		c.52G>T	p.Glu18*	stop_gained	Exon 1 of 13	NP_001339363.1
	KIZ	NM_001276389.2		c.131G>T	p.Arg44Leu	missense	Exon 1 of 11	NP_001263318.1	A0A087X251

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIZ	ENST00000619189.5	TSL:1 MANE Select	c.52G>T	p.Glu18*	stop_gained	Exon 1 of 13	ENSP00000479542.1	Q2M2Z5-1
	KIZ	ENST00000620891.4	TSL:1	c.-95G>T		5_prime_UTR	Exon 1 of 12	ENSP00000478019.1	Q2M2Z5-2
	KIZ	ENST00000962859.1		c.52G>T	p.Glu18*	stop_gained	Exon 1 of 13	ENSP00000632918.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000442 AC: 6 AN: 1356692 Hom.: 0 Cov.: 32 AF XY: 0.00000449 AC XY: 3 AN XY: 668280

African (AFR) AF: 0.00 AC: 0 AN: 27784

American (AMR) AF: 0.00 AC: 0 AN: 31660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23610

East Asian (EAS) AF: 0.00 AC: 0 AN: 30412

South Asian (SAS) AF: 0.00 AC: 0 AN: 75504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 0.00000566 AC: 6 AN: 1059364

Other (OTH) AF: 0.00 AC: 0 AN: 56082

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000359 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Retinitis pigmentosa 69 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	36
DANN	Benign	0.81
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		2.0
Vest4		0.68
GERP RS		4.1
PromoterAI		-0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs587777376; hg19: chr20-21106808;