Genetic Variant KNCN:p.Arg119Pro (chr1-46547749-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001322255.2(KNCN):c.356G>C(p.Arg119Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KNCN
NM_001322255.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32953787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2 link	c.356G>C	p.Arg119Pro	missense_variant	Exon 4 of 4	ENST00000481882.7	NP_001309184.1	A6PVL3-1
KNCN	NM_001097611.1 link	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 3		NP_001091080.1	A6PVL3-2
MKNK1-AS1	NR_038403.1 link	n.254+3981C>G		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7 link	c.356G>C	p.Arg119Pro	missense_variant	Exon 4 of 4	5	NM_001322255.2	ENSP00000419705.3		A6PVL3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1331624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

650276

African (AFR)

AF:

0.00

AC:

AN:

29412

American (AMR)

AF:

0.00

AC:

AN:

25022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19994

East Asian (EAS)

AF:

0.00

AC:

AN:

35590

South Asian (SAS)

AF:

0.00

AC:

AN:

66578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1049586

Other (OTH)

AF:

0.00

AC:

AN:

54976

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.287G>C (p.R96P) alteration is located in exon 3 (coding exon 3) of the KNCN gene. This alteration results from a G to C substitution at nucleotide position 287, causing the arginine (R) at amino acid position 96 to be replaced by a proline (P). 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

0.12

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.0

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.096

Sift

Uncertain

0.0060

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.94

.;P

Vest4

0.52

MutPred

0.22

.;Loss of MoRF binding (P = 6e-04);

MVP

0.055

MPC

0.17

ClinPred

0.60

GERP RS

2.8

Varity_R

0.44

gMVP

0.043

Mutation Taster

=92/8

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over