Variant rs202210819 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018474.6(KIZ):c.226C>T(p.Arg76Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,587,168 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

KIZ
NM_018474.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.56

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-21136463-C-T is Pathogenic according to our data. Variant chr20-21136463-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 128241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-21136463-C-T is described in Lovd as [Pathogenic]. Variant chr20-21136463-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIZ	NM_018474.6 linkuse as main transcript	c.226C>T	p.Arg76Ter	stop_gained	3/13	ENST00000619189.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIZ	ENST00000619189.5 linkuse as main transcript	c.226C>T	p.Arg76Ter	stop_gained	3/13	1	NM_018474.6	P1	Q2M2Z5-1

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000489

AC:

107

AN:

219034

Hom.:

AF XY:

0.000483

AC XY:

AN XY:

118098

show subpopulations

Gnomad AFR exome

AF:

0.0000737

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00640

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000935

Gnomad OTH exome

AF:

0.000543

GnomAD4 exome

AF:

0.000196

AC:

281

AN:

1435040

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

152

AN XY:

712486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00120

Gnomad4 ASJ exome

AF:

0.00641

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000301

Gnomad4 OTH exome

AF:

0.000572

GnomAD4 genome

AF:

0.000316

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000366

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000611

AC:

ExAC

AF:

0.000390

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 69

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 03, 2014	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The PLK1S1 c.226C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM3, PP4. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_018474.5:c.226C>T in the KIZ gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Arg76* (NM_018474.5:c.226C>T) variant in the KIZ gene has been reported in retinitis pigmentosa patients with a homozygous mutation (PMID: 24680887; 2905781). This variant is presented in the biological transcript and located at the 3/13 exon, therefore, it is predicted to lead nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 19, 2021	- -
Pathogenic, no assertion criteria provided	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 05, 2023	The homozygous p.Arg76Ter variant in KIZ was identified by our study in 2 siblings with retinitis pigmentosa. The variant has been reported in 9 individuals with retinitis pigmentosa (PMID: 28837078, 24680887, 29057815, 32052671, 31556760), segregated with disease in 2 affected relatives from 2 families (PMID: 28837078), and has been identified in 0.63% (61/9658) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202210819). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 128241) as pathogenic by GeneDx, OMIM, Sharon lab, Hadassah-Hebrew University Medical Center, and Reproductive Health Research and Development, BGI Genomics. Of the 9 affected individuals, all were homozygotes, which increases the likelihood that the p.Arg76Ter variant is pathogenic (PMID: 28837078, 24680887, 29057815, 32052671, 31556760). This nonsense variant leads to a premature termination codon at position 76, which is predicted to lead to a truncated or absent protein. Loss of function of the KIZ gene is an established disease mechanism in autosomal recessive retinitis pigmentosa. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP Criteria applied: PVS1, PM3, PP1 (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg76*) in the KIZ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIZ are known to be pathogenic (PMID: 24680887, 29057815). This variant is present in population databases (rs202210819, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 24680887, 28837078, 29057815, 31556760, 32052671; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128241). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28837078, 24680887, 29057815, 30081015, 31556760, 31456290, 34662339, 36317312, 32052671) -

KIZ-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2023

The KIZ c.226C>T variant is predicted to result in premature protein termination (p.Arg76*). This variant has been reported in the homozygous and compound heterozygous states in individuals with rod-cone dystrophy (El Shamieh et al. 2014. PubMed ID: 24680887; El Shamieh et al. 2017. PubMed ID: 29057815; Gustafson et al. 2017. PubMed ID: 28837078; Table S2 in Sharon et al. 2019. PubMed ID: 31456290). This variant is reported in 0.63% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-21117104-C-T). Nonsense variants in KIZ are expected to be pathogenic. Given the evidence, we interpret c.226C>T (p.Arg76*) as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 27, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

DANN

Benign

0.69

FATHMM_MKL

Uncertain

0.83

Vest4

0.86

GERP RS

5.5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over