Genetic Variant KNCN:p.Arg101His (chr1-46547803-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001322255.2(KNCN):c.302G>A(p.Arg101His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,457,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

KNCN
NM_001322255.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034183472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2 link	c.302G>A	p.Arg101His	missense_variant	Exon 4 of 4	ENST00000481882.7	NP_001309184.1	A6PVL3-1
KNCN	NM_001097611.1 link	c.233G>A	p.Arg78His	missense_variant	Exon 3 of 3		NP_001091080.1	A6PVL3-2
MKNK1-AS1	NR_038403.1 link	n.254+4035C>T		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7 link	c.302G>A	p.Arg101His	missense_variant	Exon 4 of 4	5	NM_001322255.2	ENSP00000419705.3		A6PVL3-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000869

AC:

AN:

80558

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

39956

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000890

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000298

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

195

AN:

1305118

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

115

AN XY:

633672

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000473

Gnomad4 FIN exome

AF:

0.0000223

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.000297

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233G>A (p.R78H) alteration is located in exon 3 (coding exon 3) of the KNCN gene. This alteration results from a G to A substitution at nucleotide position 233, causing the arginine (R) at amino acid position 78 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;D

REVEL

Benign

0.11

Sift

Benign

0.24

T;D

Sift4G

Uncertain

0.025

D;D

Polyphen

0.0020

.;B

Vest4

0.26

MVP

0.040

MPC

0.11

ClinPred

0.092

GERP RS

2.5

Varity_R

0.052

gMVP

0.085

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over