rs76371152

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144508.5(KNL1):c.727A>G(p.Ile243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,604,072 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 49 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 62 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.56

Variant links:

Genes affected

KNL1 (HGNC:24054): (kinetochore scaffold 1) The protein encoded by this gene is a component of the multiprotein assembly that is required for creation of kinetochore-microtubule attachments and chromosome segregation. The encoded protein functions as a scaffold for proteins that influence the spindle assembly checkpoint during the eukaryotic cell cycle and it interacts with at least five different kinetochore proteins and two checkpoint kinases. In adults, this gene is predominantly expressed in normal testes, various cancer cell lines and primary tumors from other tissues and is ubiquitously expressed in fetal tissues. This gene was originally identified as a fusion partner with the mixed-lineage leukemia (MLL) gene in t(11;15)(q23;q14). Mutations in this gene cause autosomal recessive primary microcephaly-4 (MCPH4). Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jan 2013]

KNL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029896498).

BP6

Variant 15-40620991-A-G is Benign according to our data. Variant chr15-40620991-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.727A>G	p.Ile243Val	missense_variant	Exon 10 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.805A>G	p.Ile269Val	missense_variant	Exon 11 of 27		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 link	c.727A>G	p.Ile243Val	missense_variant	Exon 10 of 26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2086

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0474

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00361

AC:

860

AN:

238454

Hom.:

AF XY:

0.00288

AC XY:

374

AN XY:

129840

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.00239

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00141

GnomAD4 exome

AF:

0.00161

AC:

2335

AN:

1451750

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1056

AN XY:

722256

show subpopulations

Gnomad4 AFR exome

AF:

0.0535

Gnomad4 AMR exome

AF:

0.00254

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000177

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000197

Gnomad4 OTH exome

AF:

0.00391

GnomAD4 genome

AF:

0.0138

AC:

2102

AN:

152322

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

989

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0477

Gnomad4 AMR

AF:

0.00516

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00250

Hom.:

Bravo

AF:

0.0164

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0442

AC:

162

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00426

AC:

515

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 23, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Apr 16, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary Microcephaly, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.0010

DANN

Benign

0.29

DEOGEN2

Benign

0.020

T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.46

T;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.040

N;.;N

REVEL

Benign

0.017

Sift

Benign

0.86

T;.;T

Sift4G

Benign

0.83

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.031

MVP

0.099

MPC

0.033

ClinPred

0.000026

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.018

gMVP

0.053

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

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