Genetic Variant KNCN:p.Arg101Leu (chr1-46547803-C-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.302G>T(p.Arg101Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

KNCN
NM_001322255.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68

Publications

1 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15538359).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322255.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNCN	NM_001322255.2	MANE Select	c.302G>T	p.Arg101Leu	missense	Exon 4 of 4	NP_001309184.1	A6PVL3-1
KNCN	NM_001097611.1		c.233G>T	p.Arg78Leu	missense	Exon 3 of 3	NP_001091080.1	A6PVL3-2
MKNK1-AS1	NR_038403.1		n.254+4035C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNCN	ENST00000481882.7	TSL:5 MANE Select	c.302G>T	p.Arg101Leu	missense	Exon 4 of 4	ENSP00000419705.3	A6PVL3-1
KNCN	ENST00000294445.7	TSL:1	n.161G>T		non_coding_transcript_exon	Exon 3 of 3
KNCN	ENST00000396314.3	TSL:4	c.233G>T	p.Arg78Leu	missense	Exon 3 of 3	ENSP00000379607.3	A6PVL3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

80558

AF XY:

0.0000250

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:

0.0000311

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305118

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

633672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28456

American (AMR)

AF:

0.00

AC:

AN:

20304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18972

East Asian (EAS)

AF:

0.00

AC:

AN:

35244

South Asian (SAS)

AF:

0.00

AC:

AN:

63374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3736

European-Non Finnish (NFE)

AF:

9.65e-7

AC:

AN:

1036430

Other (OTH)

AF:

0.00

AC:

AN:

53800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

0.0090

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.78

M_CAP

Benign

0.0095

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.83

PhyloP100

1.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.17

Sift

Uncertain

0.025

Sift4G

Uncertain

0.042

Polyphen

0.18

Vest4

0.43

MutPred

0.17

Loss of MoRF binding (P = 0.0019)

MVP

0.11

MPC

0.12

ClinPred

0.78

GERP RS

2.5

Varity_R

0.21

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over