chr16-27573942-C-T

Position:

chr16-27573942-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_015202.5(KATNIP):c.49C>T(p.Arg17*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,926 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 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

KATNIP
NM_015202.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.18

Variant links:

Genes affected

KATNIP (HGNC:29068): (katanin interacting protein) This gene encodes a novel, evolutionarily conserved, ciliary protein. In human hTERT-RPE1 cells, the protein is found at the base of cilia, decorating the ciliary axoneme, and enriched at the ciliary tip. The protein binds to microtubules in vitro and regulates their stability when it is overexpressed. A null mutation in this gene has been associated with Joubert syndrome, a recessive disorder that is characterized by a distinctive mid-hindbrain and cerebellar malformation and is also often associated with wider ciliopathy symptoms. Consistently, in a serum-starvation ciliogenesis assay, human fibroblast cells derived from patients with the mutation display a reduced number of ciliated cells with abnormally long cilia. [provided by RefSeq, Feb 2016]

KATNIP links:

KATNIP (HGNC:):

KATNIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.99 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-27573942-C-T is Pathogenic according to our data. Variant chr16-27573942-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 828110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KATNIP	NM_015202.5 linkuse as main transcript	c.49C>T	p.Arg17*	stop_gained	2/28	ENST00000261588.10	NP_056017.4	O60303

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KATNIP	ENST00000261588.10 linkuse as main transcript	c.49C>T	p.Arg17*	stop_gained	2/28	1	NM_015202.5	ENSP00000261588.4	O60303
KATNIP	ENST00000568258.5 linkuse as main transcript	c.34C>T	p.Arg12*	stop_gained	1/7	3		ENSP00000454884.1	H3BNJ6
KATNIP	ENST00000565672.5 linkuse as main transcript	n.19C>T		non_coding_transcript_exon_variant	1/6	3		ENSP00000455380.1	H3BPM2
KATNIP	ENST00000566023.1 linkuse as main transcript	n.87C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251454

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000506

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Arg17*) in the KIAA0556 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIAA0556 are known to be pathogenic (PMID: 26714646, 27245168). This variant is present in population databases (rs142375551, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KIAA0556-related conditions. ClinVar contains an entry for this variant (Variation ID: 828110). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	Reported in large cohort study of individuals with cardiovascular disease; however, zygosity and detailed clinical information was not provided (PMID: 31345219); 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: 31345219) -

Joubert syndrome 26

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Nov 03, 2022	The c.49C>T;p.(Arg17*) variant creates a premature translational stop signal in the KATNIP gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (Clinvar ID:828110) - PS4_supporting. The variant is present at low allele frequencies population databases (rs142375551 – gnomAD 0.0007233%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.74

Vest4

0.28

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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