chr15-40606445-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:5

Conservation

PhyloP100: -0.751

Publications

49 publications found

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 Gene-Disease associations (from GenCC):

microcephaly 4, primary, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KNL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.128G>C	p.Arg43Thr	missense_variant	Exon 4 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.128G>C	p.Arg43Thr	missense_variant	Exon 4 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.128G>C	p.Arg43Thr	missense_variant	Exon 4 of 26	1	NM_144508.5	ENSP00000382576.3		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

GnomAD2 exomes

AF:

0.737

AC:

183466

AN:

248890

AF XY:

0.752

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 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

African (AFR)

AF:

0.768

AC:

24732

AN:

32190

American (AMR)

AF:

0.511

AC:

22735

AN:

44466

Ashkenazi Jewish (ASJ)

AF:

0.807

AC:

20651

AN:

25580

East Asian (EAS)

AF:

0.309

AC:

12140

AN:

39338

South Asian (SAS)

AF:

0.761

AC:

64187

AN:

84306

European-Finnish (FIN)

AF:

0.836

AC:

44478

AN:

53230

Middle Eastern (MID)

AF:

0.823

AC:

4503

AN:

5470

European-Non Finnish (NFE)

AF:

0.843

AC:

881538

AN:

1045414

Other (OTH)

AF:

0.794

AC:

45957

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

8309

16618

24927

33236

41545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.785

AC:

119337

AN:

152082

Hom.:

47814

Cov.:

AF XY:

0.779

AC XY:

57943

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.769

AC:

31885

AN:

41454

American (AMR)

AF:

0.660

AC:

10069

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

2795

AN:

3468

East Asian (EAS)

AF:

0.323

AC:

1671

AN:

5174

South Asian (SAS)

AF:

0.727

AC:

3498

AN:

4814

European-Finnish (FIN)

AF:

0.846

AC:

8961

AN:

10588

Middle Eastern (MID)

AF:

0.833

AC:

245

AN:

294

European-Non Finnish (NFE)

AF:

0.851

AC:

57883

AN:

68006

Other (OTH)

AF:

0.776

AC:

1634

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1220

2439

3659

4878

6098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 23, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 4, primary, autosomal recessive

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.2

(source)

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

PhyloP100

-0.75

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

Mutation Taster

=99/1

polymorphism (auto)

(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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chr15-40606445-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over