rs17747633

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3775A>G(p.Lys1259Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,648 control chromosomes in the GnomAD database, including 136,887 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 9055 hom., cov: 32)

Exomes 𝑓: 0.41 ( 127832 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.866

Publications

52 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=0.0010717511).

BP6

Variant 15-40624039-A-G is Benign according to our data. Variant chr15-40624039-A-G is described in ClinVar as Benign. ClinVar VariationId is 128598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.3775A>G	p.Lys1259Glu	missense_variant	Exon 10 of 26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5 link	c.3853A>G	p.Lys1285Glu	missense_variant	Exon 11 of 27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 link	c.3775A>G	p.Lys1259Glu	missense_variant	Exon 10 of 26	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46528

AN:

151992

Hom.:

9060

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0899

Gnomad AMI

AF:

0.370

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.0776

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.441

Gnomad OTH

AF:

0.339

GnomAD2 exomes

AF:

0.329

AC:

81977

AN:

249074

AF XY:

0.337

show subpopulations

Gnomad AFR exome

AF:

0.0847

Gnomad AMR exome

AF:

0.221

Gnomad ASJ exome

AF:

0.394

Gnomad EAS exome

AF:

0.0835

Gnomad FIN exome

AF:

0.382

Gnomad NFE exome

AF:

0.432

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.405

AC:

592418

AN:

1461538

Hom.:

127832

Cov.:

AF XY:

0.403

AC XY:

292785

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.0813

AC:

2721

AN:

33476

American (AMR)

AF:

0.231

AC:

10352

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.398

AC:

10412

AN:

26130

East Asian (EAS)

AF:

0.0598

AC:

2372

AN:

39684

South Asian (SAS)

AF:

0.267

AC:

23031

AN:

86248

European-Finnish (FIN)

AF:

0.378

AC:

20147

AN:

53356

Middle Eastern (MID)

AF:

0.373

AC:

2152

AN:

5768

European-Non Finnish (NFE)

AF:

0.448

AC:

498497

AN:

1111768

Other (OTH)

AF:

0.376

AC:

22734

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

19318

38635

57953

77270

96588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14690

29380

44070

58760

73450

<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:

0.306

AC:

46511

AN:

152110

Hom.:

9055

Cov.:

AF XY:

0.302

AC XY:

22441

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0897

AC:

3724

AN:

41532

American (AMR)

AF:

0.304

AC:

4638

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1389

AN:

3466

East Asian (EAS)

AF:

0.0770

AC:

400

AN:

5192

South Asian (SAS)

AF:

0.264

AC:

1272

AN:

4826

European-Finnish (FIN)

AF:

0.377

AC:

3988

AN:

10574

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.441

AC:

29952

AN:

67934

Other (OTH)

AF:

0.336

AC:

709

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1502

3004

4505

6007

7509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.392

Hom.:

30095

Bravo

AF:

0.288

TwinsUK

AF:

0.450

AC:

1668

ALSPAC

AF:

0.443

AC:

1708

ESP6500AA

AF:

0.0965

AC:

357

ESP6500EA

AF:

0.433

AC:

3546

ExAC

AF:

0.327

AC:

39446

Asia WGS

AF:

0.145

AC:

504

AN:

3478

EpiCase

AF:

0.440

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

Aug 15, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

0.0011

T;T;T

MetaSVM

Benign

-0.91

PhyloP100

0.87

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.074

Sift

Benign

0.035

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.12

MPC

0.052

ClinPred

0.0073

GERP RS

3.4

Varity_R

0.10

gMVP

0.19

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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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