rs202012571

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_144508.5(KNL1):c.2268A>G(p.Ser756Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,008 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 43 hom. )

Consequence

KNL1
NM_144508.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.11

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 15-40622532-A-G is Benign according to our data. Variant chr15-40622532-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210565.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP7

Synonymous conserved (PhyloP=1.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00142 (217/152322) while in subpopulation SAS AF = 0.0215 (104/4828). AF 95% confidence interval is 0.0182. There are 5 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.2268A>G	p.Ser756Ser	synonymous_variant	Exon 10 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.2346A>G	p.Ser782Ser	synonymous_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.2268A>G	p.Ser756Ser	synonymous_variant	Exon 10 of 26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00366

AC:

911

AN:

249198

AF XY:

0.00465

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00218

AC:

3192

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

2094

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33474

American (AMR)

AF:

0.00165

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0210

AC:

1810

AN:

86244

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000900

AC:

1001

AN:

1111902

Other (OTH)

AF:

0.00272

AC:

164

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

161

322

483

644

805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00142

AC:

217

AN:

152322

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41580

American (AMR)

AF:

0.00124

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0215

AC:

104

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00142

Hom.:

Bravo

AF:

0.000975

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 07, 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

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.5

(source)

DANN

Benign

0.58

PhyloP100

1.1

Mutation Taster

=92/8

polymorphism

(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