Genetic Variant KNCN:p.Arg11Cys (chr1-46551185-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.31C>T(p.Arg11Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,457,820 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KNCN
NM_001322255.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

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=0.23423493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2 link	c.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 4	ENST00000481882.7	NP_001309184.1	A6PVL3-1
KNCN	NM_001097611.1 link	c.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 3		NP_001091080.1	A6PVL3-2
MKNK1-AS1	NR_038403.1 link	n.255-7040G>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.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 4	5	NM_001322255.2	ENSP00000419705.3		A6PVL3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000820

AC:

AN:

243842

AF XY:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1457820

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33252

American (AMR)

AF:

0.0000226

AC:

AN:

44256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39254

South Asian (SAS)

AF:

0.00

AC:

AN:

85660

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1110258

Other (OTH)

AF:

0.00

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.31C>T (p.R11C) alteration is located in exon 1 (coding exon 1) of the KNCN gene. This alteration results from a C to T substitution at nucleotide position 31, causing the arginine (R) at amino acid position 11 to be replaced by a cysteine (C). 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

-0.068

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.66

PhyloP100

3.8

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.0070

.;B

Vest4

0.28

MutPred

0.29

Loss of disorder (P = 0.033);Loss of disorder (P = 0.033);

MVP

0.38

MPC

0.53

ClinPred

0.94

GERP RS

4.5

PromoterAI

-0.057

Neutral

(source)

Varity_R

0.22

gMVP

0.41

Mutation Taster

=94/6

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

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

1-46551185-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