rs142872154

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_144508.5(KNL1):c.6482A>G(p.Asp2161Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000187 in 1,611,174 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00092 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

KNL1
NM_144508.5 missense, splice_region

Scores

Splicing: ADA: 0.4211

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:1

Conservation

PhyloP100: 5.34

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03363198).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00092 (140/152226) while in subpopulation AFR AF = 0.00325 (135/41538). AF 95% confidence interval is 0.0028. There are 1 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.6482A>G	p.Asp2161Gly	missense_variant, splice_region_variant	Exon 22 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.6560A>G	p.Asp2187Gly	missense_variant, splice_region_variant	Exon 23 of 27		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KNL1	ENST00000399668.7 link	c.6482A>G	p.Asp2161Gly	missense_variant, splice_region_variant	Exon 22 of 26	1	NM_144508.5	ENSP00000382576.3	Q8NG31-2
KNL1	ENST00000346991.9 link	c.6560A>G	p.Asp2187Gly	missense_variant, splice_region_variant	Exon 23 of 27	1		ENSP00000335463.6	Q8NG31-1
KNL1	ENST00000526913.5 link	n.3614A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 18	1		ENSP00000432565.1	H0YCZ2
KNL1	ENST00000532347.1 link	n.562A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.000914

AC:

139

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000261

AC:

AN:

248892

AF XY:

0.000229

show subpopulations

Gnomad AFR exome

AF:

0.00356

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000110

AC:

161

AN:

1458948

Hom.:

Cov.:

AF XY:

0.0000868

AC XY:

AN XY:

726048

show subpopulations

African (AFR)

AF:

0.00350

AC:

117

AN:

33420

American (AMR)

AF:

0.000246

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1109904

Other (OTH)

AF:

0.000298

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000920

AC:

140

AN:

152226

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00325

AC:

135

AN:

41538

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000254

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.00219

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000298

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly 4, primary, autosomal recessive

Pathogenic:1Uncertain:3

Oct 26, 2015

Molecular Genetics Pathology Laboratory, University Of Arkansas for Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c. 6560A>G is classified as of unknown significance. Per ACMG criteria, it does have silico prediction criteria PP3. The variant is predicted pathogenic by SIFT, Mutation tasting, Provean (-3.624), and PolyPhen-2 (0.999). The physiochemical difference between Aspartic acid and Glycine is moderate (Grantham score=94) and amino acid analysis conservation by Alamut indicates that the wild type amino acid is moderately conserved. The c.6560A>G variant is very rare in the general population, but particularly found in patients of African ancestry with a reported heterozygous median allele frequency of 0.0034 (33/9694 alleles) in the Exome Aggregation Consortium and 0.0022 (8/3660) in the Exome Variant Server for people of this ancestry. -

Dec 24, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 01, 2022

Daryl Scott Lab, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28901661, 22983954, 27149178, 36474027) -

not specified

Uncertain:1

Jun 26, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.2

PhyloP100

5.3

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.24

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.071

T;T

Polyphen

1.0

D;D

Vest4

0.81

MVP

0.71

MPC

0.075

ClinPred

0.091

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.66

gMVP

0.37

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.42

dbscSNV1_RF

Benign

0.43

SpliceAI score (max)

0.060

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