ENST00000346991.9:c.305G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000346991.9(KNL1):c.305G>A(p.Arg102Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 454,554 control chromosomes in the GnomAD database, including 212 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 0.031 ( 131 hom., cov: 32)

Exomes 𝑓: 0.016 ( 81 hom. )

Consequence

KNL1
ENST00000346991.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.22

Publications

2 publications found

Variant links:

COSMIC-nc: COSV61151110

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=0.00364846).

BP6

Variant 15-40610853-G-A is Benign according to our data. Variant chr15-40610853-G-A is described in ClinVar as Benign. ClinVar VariationId is 128580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.250+556G>A		intron_variant	Intron 6 of 25	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.305G>A	p.Arg102Gln	missense_variant	Exon 7 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.250+556G>A		intron_variant	Intron 6 of 25	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.0314

AC:

4775

AN:

152034

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0725

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0264

GnomAD2 exomes

AF:

0.0155

AC:

1981

AN:

127888

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.0732

Gnomad AMR exome

AF:

0.00912

Gnomad ASJ exome

AF:

0.0254

Gnomad EAS exome

AF:

0.000192

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0160

AC:

4843

AN:

302402

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

2686

AN XY:

172296

show subpopulations

African (AFR)

AF:

0.0684

AC:

586

AN:

8568

American (AMR)

AF:

0.00928

AC:

253

AN:

27270

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

261

AN:

10778

East Asian (EAS)

AF:

0.000109

AC:

AN:

9192

South Asian (SAS)

AF:

0.00965

AC:

576

AN:

59678

European-Finnish (FIN)

AF:

0.0121

AC:

149

AN:

12362

Middle Eastern (MID)

AF:

0.0219

AC:

AN:

1778

European-Non Finnish (NFE)

AF:

0.0173

AC:

2742

AN:

158690

Other (OTH)

AF:

0.0168

AC:

236

AN:

14086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

228

457

685

914

1142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0314

AC:

4782

AN:

152152

Hom.:

131

Cov.:

AF XY:

0.0312

AC XY:

2318

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0725

AC:

3008

AN:

41502

American (AMR)

AF:

0.0146

AC:

223

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00955

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0162

AC:

172

AN:

10596

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1152

AN:

67998

Other (OTH)

AF:

0.0261

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

229

457

686

914

1143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0282

Hom.:

Bravo

AF:

0.0319

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0125

AC:

ExAC

AF:

0.0122

AC:

171

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 28, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 24, 2014

Genetic Services Laboratory, University of Chicago

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

-0.68

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.10

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.016

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.94

PhyloP100

-1.2

PROVEAN

Benign

-0.020

REVEL

Benign

0.042

Sift

Benign

0.34

Sift4G

Benign

0.55

Polyphen

0.19

Vest4

0.048

MPC

0.041

ClinPred

0.0061

GERP RS

-0.85

Varity_R

0.045

gMVP

0.052

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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