dbSNP rs587777377: KIZ:p.Lys40IlefsTer14 (chr20-21132125-AAACT-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_018474.6(KIZ):c.119_122delAACT(p.Lys40IlefsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.000104 in 1,464,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KIZ
NM_018474.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.98

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 20-21132125-AAACT-A is Pathogenic according to our data. Variant chr20-21132125-AAACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 128243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-21132125-AAACT-A is described in Lovd as [Likely_pathogenic]. Variant chr20-21132125-AAACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIZ	NM_018474.6 link	c.119_122delAACT	p.Lys40IlefsTer14	frameshift_variant	Exon 2 of 13	ENST00000619189.5	NP_060944.3	Q2M2Z5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIZ	ENST00000619189.5 link	c.119_122delAACT	p.Lys40IlefsTer14	frameshift_variant	Exon 2 of 13	1	NM_018474.6	ENSP00000479542.1		Q2M2Z5-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000331

AC:

AN:

151254

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

79670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000829

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

139

AN:

1311912

Hom.:

AF XY:

0.000108

AC XY:

AN XY:

651088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.000127

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 69

Pathogenic:1

Apr 03, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys40Ilefs*14) 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 (rs587777377, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 24680887). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 128243). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Apr 26, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Apr 12, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys40IlefsX14 variant in KIZ has been reported in 7 individuals with retinitis pigmentosa, including three homozygotes and two compound heterozygotes with a second pathogenic KIZ variant (Lin 2020 PMID: 32052671, El Shamieh 2014 PMID: 24680887, Blueprint Genetics data, Invitae data). It has also been identified in 0.009% (7/75782) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 40 and leads to a premature termination codon 14 amino acids downstream. Loss of function of the KIZ gene is associated with autosomal recessive retinitis pigmentosa. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP criteria applied: PM3_Strong, PVS1_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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