Genetic Variant KNCN:p.Pro116Leu (chr1-46547758-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001322255.2(KNCN):c.347C>T(p.Pro116Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000466 in 1,480,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

KNCN
NM_001322255.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Publications

0 publications found

Variant links:

Genes affected

KNCN (HGNC:26488): (kinocilin) Predicted to be located in apical part of cell; cytoplasm; and microtubule cytoskeleton. Predicted to be active in several cellular components, including apical plasma membrane; cytoskeleton; and kinocilium. [provided by Alliance of Genome Resources, Apr 2022]

KNCN links:

MKNK1-AS1 (HGNC:44129): (MKNK1 antisense RNA 1)

MKNK1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13448596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2 link	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 4	ENST00000481882.7	NP_001309184.1	A6PVL3-1
KNCN	NM_001097611.1 link	c.278C>T	p.Pro93Leu	missense_variant	Exon 3 of 3		NP_001091080.1	A6PVL3-2
MKNK1-AS1	NR_038403.1 link	n.254+3990G>A		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7 link	c.347C>T	p.Pro116Leu	missense_variant	Exon 4 of 4	5	NM_001322255.2	ENSP00000419705.3		A6PVL3-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000420

AC:

AN:

95144

AF XY:

0.0000419

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 FIN exome

AF:

0.0000867

Gnomad NFE exome

AF:

0.0000781

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000489

AC:

AN:

1328176

Hom.:

Cov.:

AF XY:

0.0000447

AC XY:

AN XY:

648188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29258

American (AMR)

AF:

0.00

AC:

AN:

24358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19766

East Asian (EAS)

AF:

0.00

AC:

AN:

35624

South Asian (SAS)

AF:

0.00

AC:

AN:

65910

European-Finnish (FIN)

AF:

0.0000878

AC:

AN:

45552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4506

European-Non Finnish (NFE)

AF:

0.0000582

AC:

AN:

1048368

Other (OTH)

AF:

0.00

AC:

AN:

54834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000271

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.278C>T (p.P93L) alteration is located in exon 3 (coding exon 3) of the KNCN gene. This alteration results from a C to T substitution at nucleotide position 278, causing the proline (P) at amino acid position 93 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

T;.

Eigen

Benign

-0.046

Eigen_PC

Benign

0.0033

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.82

PhyloP100

4.2

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.30

.;B

Vest4

0.41

MVP

0.099

MPC

0.47

ClinPred

0.44

GERP RS

3.7

Varity_R

0.17

gMVP

0.057

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

1-46547758-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over