Genetic Variant KNCN:p.Arg101Pro (chr1-46547803-C-G) – 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>C(p.Arg101Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000015 ( 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:

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=0.19745451).

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>C	p.Arg101Pro	missense	Exon 4 of 4	NP_001309184.1	A6PVL3-1
KNCN	NM_001097611.1		c.233G>C	p.Arg78Pro	missense	Exon 3 of 3	NP_001091080.1	A6PVL3-2
MKNK1-AS1	NR_038403.1		n.254+4035C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNCN	ENST00000481882.7	TSL:5 MANE Select	c.302G>C	p.Arg101Pro	missense	Exon 4 of 4	ENSP00000419705.3	A6PVL3-1
KNCN	ENST00000294445.7	TSL:1	n.161G>C		non_coding_transcript_exon	Exon 3 of 3
KNCN	ENST00000396314.3	TSL:4	c.233G>C	p.Arg78Pro	missense	Exon 3 of 3	ENSP00000379607.3	A6PVL3-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

80558

AF XY:

0.0000250

show subpopulations

Gnomad AFR exome

AF:

0.000155

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000153

AC:

AN:

1305118

Hom.:

Cov.:

AF XY:

0.00000316

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:

0.0000186

AC:

AN:

53800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

0.0060

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.74

M_CAP

Benign

0.011

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.89

PhyloP100

1.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.37

Sift

Uncertain

0.019

Sift4G

Uncertain

0.037

Polyphen

0.61

Vest4

0.43

MutPred

0.20

Loss of MoRF binding (P = 3e-04)

MVP

0.19

MPC

0.15

ClinPred

0.80

GERP RS

2.5

Varity_R

0.70

gMVP

0.16

Mutation Taster

=90/10

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