NM_018474.6:c.226C>T

Variant names:

• chr20-21136463-C-T
• rs202210819
• NM_018474.6:c.226C>T

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.226C>T​(p.Arg76*) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.56
• Publications: 17 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-21136463-C-T is Pathogenic according to our data. Variant chr20-21136463-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 128241.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.226C>T	p.Arg76*	stop_gained	Exon 3 of 13	NP_060944.3
	KIZ	NM_001352436.2		c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001339365.1
	KIZ	NM_001352434.2		c.226C>T	p.Arg76*	stop_gained	Exon 3 of 13	NP_001339363.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIZ	ENST00000619189.5	TSL:1 MANE Select	c.226C>T	p.Arg76*	stop_gained	Exon 3 of 13	ENSP00000479542.1	Q2M2Z5-1
	KIZ	ENST00000620891.4	TSL:1	c.6+4304C>T		intron	N/A	ENSP00000478019.1	Q2M2Z5-2
	KIZ	ENST00000962859.1		c.226C>T	p.Arg76*	stop_gained	Exon 3 of 13	ENSP00000632918.1

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152128 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000489 AC: 107 AN: 219034 AF XY: 0.000483

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 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.: 0 Cov.: 27 AF XY: 0.000213 AC XY: 152 AN XY: 712486

African (AFR) AF: 0.00 AC: 0 AN: 33094

American (AMR) AF: 0.00120 AC: 50 AN: 41664

Ashkenazi Jewish (ASJ) AF: 0.00641 AC: 164 AN: 25598

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.00 AC: 0 AN: 83084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000301 AC: 33 AN: 1094614

Other (OTH) AF: 0.000572 AC: 34 AN: 59472

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74300

African (AFR) AF: 0.0000966 AC: 4 AN: 41414

American (AMR) AF: 0.00111 AC: 17 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000611 AC: 5

ExAC AF: 0.000390 AC: 47

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Retinitis pigmentosa 69 (6)
2	-	-	not provided (2)
1	-	-	KIZ-related disorder (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	35
DANN	Benign	0.69
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		1.6
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

Other links and lift over

dbSNP: rs202210819; hg19: chr20-21117104;