rs8041534

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144508.5(KNL1):c.2583T>G(p.Thr861Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,612,450 control chromosomes in the GnomAD database, including 128,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11755 hom., cov: 32)

Exomes 𝑓: 0.40 ( 117043 hom. )

Consequence

KNL1
NM_144508.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.289

Publications

32 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -21 ACMG points.

BP4

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

BP6

Variant 15-40622847-T-G is Benign according to our data. Variant chr15-40622847-T-G is described in ClinVar as Benign. ClinVar VariationId is 128593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.289 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144508.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.2583T>G	p.Thr861Thr	synonymous	Exon 10 of 26	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.2661T>G	p.Thr887Thr	synonymous	Exon 11 of 27	NP_733468.3	Q8NG31-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNL1	ENST00000399668.7	TSL:1 MANE Select	c.2583T>G	p.Thr861Thr	synonymous	Exon 10 of 26	ENSP00000382576.3	Q8NG31-2
KNL1	ENST00000346991.9	TSL:1	c.2661T>G	p.Thr887Thr	synonymous	Exon 11 of 27	ENSP00000335463.6	Q8NG31-1
KNL1	ENST00000533001.1	TSL:1	n.2728T>G		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.390

AC:

59220

AN:

151888

Hom.:

11740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.370

Gnomad AMI

AF:

0.393

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.246

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.469

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.409

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.386

AC:

95945

AN:

248550

AF XY:

0.399

show subpopulations

Gnomad AFR exome

AF:

0.367

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.416

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.460

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.396

GnomAD4 exome

AF:

0.397

AC:

579113

AN:

1460444

Hom.:

117043

Cov.:

AF XY:

0.401

AC XY:

291362

AN XY:

726558

show subpopulations

African (AFR)

AF:

0.370

AC:

12373

AN:

33412

American (AMR)

AF:

0.266

AC:

11876

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

10681

AN:

26080

East Asian (EAS)

AF:

0.250

AC:

9929

AN:

39676

South Asian (SAS)

AF:

0.493

AC:

42498

AN:

86146

European-Finnish (FIN)

AF:

0.458

AC:

24461

AN:

53366

Middle Eastern (MID)

AF:

0.438

AC:

2522

AN:

5758

European-Non Finnish (NFE)

AF:

0.397

AC:

440646

AN:

1111084

Other (OTH)

AF:

0.400

AC:

24127

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17787

35574

53360

71147

88934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13564

27128

40692

54256

67820

<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:

0.390

AC:

59271

AN:

152006

Hom.:

11755

Cov.:

AF XY:

0.392

AC XY:

29132

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.370

AC:

15365

AN:

41478

American (AMR)

AF:

0.328

AC:

5001

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1405

AN:

3468

East Asian (EAS)

AF:

0.246

AC:

1275

AN:

5182

South Asian (SAS)

AF:

0.460

AC:

2217

AN:

4820

European-Finnish (FIN)

AF:

0.469

AC:

4958

AN:

10566

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.409

AC:

27765

AN:

67912

Other (OTH)

AF:

0.373

AC:

789

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1882

3763

5645

7526

9408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.394

Hom.:

18944

Bravo

AF:

0.373

Asia WGS

AF:

0.373

AC:

1296

AN:

3478

EpiCase

AF:

0.402

EpiControl

AF:

0.398

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly 4, primary, autosomal recessive (2)

not provided (2)

not specified (1)

Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.0

(source)

DANN

Benign

0.51

PhyloP100

-0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over