15-40608876-C-T

Position:

chr15-40608876-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_144508.5(KNL1):c.165C>T(p.Asn55Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,610,642 control chromosomes in the GnomAD database, including 10 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 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0018 ( 9 hom. )

Consequence

KNL1
NM_144508.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.541

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 links:

KNL1 (HGNC:):

KNL1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 15-40608876-C-T is Benign according to our data. Variant chr15-40608876-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 315843.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr15-40608876-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.541 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00139 (212/152122) while in subpopulation SAS AF= 0.00518 (25/4824). AF 95% confidence interval is 0.0036. There are 1 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5 linkuse as main transcript	c.165C>T	p.Asn55Asn	synonymous_variant	5/26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 linkuse as main transcript	c.165C>T	p.Asn55Asn	synonymous_variant	5/27		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 linkuse as main transcript	c.165C>T	p.Asn55Asn	synonymous_variant	5/26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00194

AC:

480

AN:

247464

Hom.:

AF XY:

0.00238

AC XY:

320

AN XY:

134682

show subpopulations

Gnomad AFR exome

AF:

0.000262

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.000223

Gnomad SAS exome

AF:

0.00613

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.00179

AC:

2612

AN:

1458520

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1485

AN XY:

725710

show subpopulations

Gnomad4 AFR exome

AF:

0.000688

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00658

Gnomad4 FIN exome

AF:

0.000209

Gnomad4 NFE exome

AF:

0.00159

Gnomad4 OTH exome

AF:

0.00221

GnomAD4 genome

AF:

0.00139

AC:

212

AN:

152122

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00182

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00130

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00175

EpiControl

AF:

0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KNL1: BP4, BP7 -

Primary Microcephaly, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

5.1

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over