rs17747633

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -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. 12/19 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

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=0.0010717511).

BP6

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

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	Q8NG31-2
KNL1	NM_170589.5 link	c.3853A>G	p.Lys1285Glu	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.3775A>G	p.Lys1259Glu	missense_variant	Exon 10 of 26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

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

GnomAD3 exomes

AF:

0.329

AC:

81977

AN:

249074

Hom.:

15733

AF XY:

0.337

AC XY:

45495

AN XY:

135168

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 SAS exome

AF:

0.269

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

Gnomad4 AFR exome

AF:

0.0813

Gnomad4 AMR exome

AF:

0.231

Gnomad4 ASJ exome

AF:

0.398

Gnomad4 EAS exome

AF:

0.0598

Gnomad4 SAS exome

AF:

0.267

Gnomad4 FIN exome

AF:

0.378

Gnomad4 NFE exome

AF:

0.448

Gnomad4 OTH exome

AF:

0.376

GnomAD4 genome

AF:

0.306

AC:

46511

AN:

152110

Hom.:

9055

Cov.:

AF XY:

0.302

AC XY:

22441

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0897

Gnomad4 AMR

AF:

0.304

Gnomad4 ASJ

AF:

0.401

Gnomad4 EAS

AF:

0.0770

Gnomad4 SAS

AF:

0.264

Gnomad4 FIN

AF:

0.377

Gnomad4 NFE

AF:

0.441

Gnomad4 OTH

AF:

0.336

Alfa

AF:

0.410

Hom.:

21188

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

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

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

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