rs7177192

Positions:

Variant summary

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

The NM_144508.5(KNL1):c.128G>C(p.Arg43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 1,539,926 control chromosomes in the GnomAD database, including 509,570 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 Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 47814 hom., cov: 32)

Exomes 𝑓: 0.81 ( 461756 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.751

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=8.111408E-7).

BP6

Variant 15-40606445-G-C is Benign according to our data. Variant chr15-40606445-G-C is described in ClinVar as [Benign]. Clinvar id is 128586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40606445-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5 linkuse as main transcript	c.128G>C	p.Arg43Thr	missense_variant	4/26	ENST00000399668.7
KNL1	NM_170589.5 linkuse as main transcript	c.128G>C	p.Arg43Thr	missense_variant	4/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7 linkuse as main transcript	c.128G>C	p.Arg43Thr	missense_variant	4/26	1	NM_144508.5	A2	Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.785

AC:

119256

AN:

151964

Hom.:

47776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.769

Gnomad AMI

AF:

0.763

Gnomad AMR

AF:

0.660

Gnomad ASJ

AF:

0.806

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.726

Gnomad FIN

AF:

0.846

Gnomad MID

AF:

0.845

Gnomad NFE

AF:

0.851

Gnomad OTH

AF:

0.776

GnomAD3 exomes

AF:

0.737

AC:

183466

AN:

248890

Hom.:

71550

AF XY:

0.752

AC XY:

101611

AN XY:

135054

show subpopulations

Gnomad AFR exome

AF:

0.765

Gnomad AMR exome

AF:

0.490

Gnomad ASJ exome

AF:

0.810

Gnomad EAS exome

AF:

0.322

Gnomad SAS exome

AF:

0.756

Gnomad FIN exome

AF:

0.842

Gnomad NFE exome

AF:

0.840

Gnomad OTH exome

AF:

0.785

GnomAD4 exome

AF:

0.808

AC:

1120921

AN:

1387844

Hom.:

461756

Cov.:

AF XY:

0.809

AC XY:

561286

AN XY:

693934

show subpopulations

Gnomad4 AFR exome

AF:

0.768

Gnomad4 AMR exome

AF:

0.511

Gnomad4 ASJ exome

AF:

0.807

Gnomad4 EAS exome

AF:

0.309

Gnomad4 SAS exome

AF:

0.761

Gnomad4 FIN exome

AF:

0.836

Gnomad4 NFE exome

AF:

0.843

Gnomad4 OTH exome

AF:

0.794

GnomAD4 genome

AF:

0.785

AC:

119337

AN:

152082

Hom.:

47814

Cov.:

AF XY:

0.779

AC XY:

57943

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.769

Gnomad4 AMR

AF:

0.660

Gnomad4 ASJ

AF:

0.806

Gnomad4 EAS

AF:

0.323

Gnomad4 SAS

AF:

0.727

Gnomad4 FIN

AF:

0.846

Gnomad4 NFE

AF:

0.851

Gnomad4 OTH

AF:

0.776

Alfa

AF:

0.822

Hom.:

38977

Bravo

AF:

0.761

TwinsUK

AF:

0.850

AC:

3151

ALSPAC

AF:

0.845

AC:

3257

ESP6500AA

AF:

0.773

AC:

2788

ESP6500EA

AF:

0.844

AC:

6866

ExAC

AF:

0.746

AC:

90038

Asia WGS

AF:

0.548

AC:

1907

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 23, 2013

- -

Primary Microcephaly, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Microcephaly 4, primary, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.2

DANN

Benign

0.30

DEOGEN2

Benign

0.017

T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.095

T;T;T

MetaRNN

Benign

8.1e-7

T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.39

PROVEAN

Benign

1.4

N;N;N

REVEL

Benign

0.013

Sift

Benign

0.53

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.066

MPC

0.048

ClinPred

0.0024

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.039

gMVP

0.13

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