16-27749769-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015202.5(KATNIP):c.2809G>T(p.Asp937Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,610,308 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D937N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 10 hom. )

Consequence

KATNIP
NM_015202.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.56

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 26
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KATNIP links:

ENSG00000305858 (HGNC:):

ENSG00000305858 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036624074).

BP6

Variant 16-27749769-G-T is Benign according to our data. Variant chr16-27749769-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 599465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00159 (242/152270) while in subpopulation SAS AF = 0.00644 (31/4816). AF 95% confidence interval is 0.00466. There are 3 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015202.5. 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
	KATNIP	NM_015202.5	MANE Select	c.2809G>T	p.Asp937Tyr	missense	Exon 16 of 28	NP_056017.4	O60303

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KATNIP	ENST00000261588.10	TSL:1 MANE Select	c.2809G>T	p.Asp937Tyr	missense	Exon 16 of 28	ENSP00000261588.4	O60303
KATNIP	ENST00000862512.1		c.2677G>T	p.Asp893Tyr	missense	Exon 15 of 27	ENSP00000532571.1
KATNIP	ENST00000573850.1	TSL:5	n.914G>T		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00255

AC:

632

AN:

247496

AF XY:

0.00298

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00207

AC:

3016

AN:

1458038

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

1624

AN XY:

724908

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33410

American (AMR)

AF:

0.00149

AC:

AN:

44412

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

292

AN:

25824

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39652

South Asian (SAS)

AF:

0.00478

AC:

409

AN:

85620

European-Finnish (FIN)

AF:

0.000995

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00176

AC:

1950

AN:

1109864

Other (OTH)

AF:

0.00282

AC:

170

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

193

386

579

772

965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152270

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41568

American (AMR)

AF:

0.000850

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00644

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68022

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00155

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.9

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0071

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.60

M_CAP

Benign

0.024

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

1.6

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.4

REVEL

Benign

0.039

Sift

Uncertain

0.016

Sift4G

Uncertain

0.022

Polyphen

0.017

Vest4

0.18

MVP

0.12

MPC

0.56

ClinPred

0.021

GERP RS

2.6

Varity_R

0.083

gMVP

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over