NM_144508.5:c.2310C>T

Variant names:

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.2310C>T(p.Val770Val) 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 1,611,804 control chromosomes in the GnomAD database, including 128,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11733 hom., cov: 32)

Exomes 𝑓: 0.40 ( 116886 hom. )

Consequence

KNL1
NM_144508.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.569

Publications

35 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 15-40622574-C-T is Benign according to our data. Variant chr15-40622574-C-T is described in ClinVar as Benign. ClinVar VariationId is 128590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.569 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.2310C>T	p.Val770Val	synonymous_variant	Exon 10 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.2388C>T	p.Val796Val	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.2310C>T	p.Val770Val	synonymous_variant	Exon 10 of 26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.390

AC:

59153

AN:

151824

Hom.:

11718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.369

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.246

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.470

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.409

Gnomad OTH

AF:

0.370

GnomAD2 exomes

AF:

0.386

AC:

95679

AN:

247606

AF XY:

0.399

show subpopulations

Gnomad AFR exome

AF:

0.364

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.419

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.461

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.398

GnomAD4 exome

AF:

0.396

AC:

578767

AN:

1459860

Hom.:

116886

Cov.:

AF XY:

0.401

AC XY:

291157

AN XY:

726232

show subpopulations

African (AFR)

AF:

0.368

AC:

12290

AN:

33394

American (AMR)

AF:

0.267

AC:

11876

AN:

44402

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

10663

AN:

26002

East Asian (EAS)

AF:

0.250

AC:

9921

AN:

39672

South Asian (SAS)

AF:

0.492

AC:

42366

AN:

86050

European-Finnish (FIN)

AF:

0.459

AC:

24472

AN:

53374

Middle Eastern (MID)

AF:

0.438

AC:

2520

AN:

5758

European-Non Finnish (NFE)

AF:

0.397

AC:

440551

AN:

1110920

Other (OTH)

AF:

0.400

AC:

24108

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18029

36059

54088

72118

90147

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:

59204

AN:

151944

Hom.:

11733

Cov.:

AF XY:

0.392

AC XY:

29086

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.369

AC:

15293

AN:

41440

American (AMR)

AF:

0.328

AC:

5006

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1404

AN:

3470

East Asian (EAS)

AF:

0.246

AC:

1274

AN:

5176

South Asian (SAS)

AF:

0.459

AC:

2211

AN:

4818

European-Finnish (FIN)

AF:

0.470

AC:

4957

AN:

10544

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.409

AC:

27777

AN:

67920

Other (OTH)

AF:

0.374

AC:

788

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1843

3685

5528

7370

9213

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.:

36478

Bravo

AF:

0.372

Asia WGS

AF:

0.375

AC:

1304

AN:

3478

EpiCase

AF:

0.401

EpiControl

AF:

0.398

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

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

Apr 25, 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

- -

Microcephaly 4, primary, autosomal recessive

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.3

(source)

DANN

Benign

0.47

PhyloP100

0.57

Mutation Taster

=98/2

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

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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