chr15-40606445-G-C

Variant names:

• chr15-40606445-G-C
• rs7177192
• NM_144508.5:c.128G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144508.5(KNL1):​c.128G>C​(p.Arg43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 1,539,926 control chromosomes in the GnomAD database, including 509,570 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47814 hom., cov: 32)
  • Exomes 𝑓: 0.81 (461756 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.751
• Publications: 49 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.111408E-7).
• BP6: Variant 15-40606445-G-C is Benign according to our data. Variant chr15-40606445-G-C is described in ClinVar as Benign. ClinVar VariationId is 128586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.845 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.128G>C	p.Arg43Thr	missense	Exon 4 of 26	NP_653091.3
	KNL1	NM_170589.5		c.128G>C	p.Arg43Thr	missense	Exon 4 of 27	NP_733468.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.128G>C	p.Arg43Thr	missense	Exon 4 of 26	ENSP00000382576.3
	KNL1	ENST00000346991.9	TSL:1	c.128G>C	p.Arg43Thr	missense	Exon 4 of 27	ENSP00000335463.6
	KNL1	ENST00000533001.1	TSL:1	n.273G>C		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119256 AN: 151964 Hom.: 47776 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.737 AC: 183466 AN: 248890 AF XY: 0.752

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.842

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.785

GnomAD4 exome AF: 0.808 AC: 1120921 AN: 1387844 Hom.: 461756 Cov.: 22 AF XY: 0.809 AC XY: 561286 AN XY: 693934

African (AFR) AF: 0.768 AC: 24732 AN: 32190

American (AMR) AF: 0.511 AC: 22735 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 20651 AN: 25580

East Asian (EAS) AF: 0.309 AC: 12140 AN: 39338

South Asian (SAS) AF: 0.761 AC: 64187 AN: 84306

European-Finnish (FIN) AF: 0.836 AC: 44478 AN: 53230

Middle Eastern (MID) AF: 0.823 AC: 4503 AN: 5470

European-Non Finnish (NFE) AF: 0.843 AC: 881538 AN: 1045414

Other (OTH) AF: 0.794 AC: 45957 AN: 57850

GnomAD4 genome AF: 0.785 AC: 119337 AN: 152082 Hom.: 47814 Cov.: 32 AF XY: 0.779 AC XY: 57943 AN XY: 74336

African (AFR) AF: 0.769 AC: 31885 AN: 41454

American (AMR) AF: 0.660 AC: 10069 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2795 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1671 AN: 5174

South Asian (SAS) AF: 0.727 AC: 3498 AN: 4814

European-Finnish (FIN) AF: 0.846 AC: 8961 AN: 10588

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57883 AN: 68006

Other (OTH) AF: 0.776 AC: 1634 AN: 2106

Alfa AF: 0.822 Hom.: 38977

Bravo AF: 0.761

TwinsUK AF: 0.850 AC: 3151

ALSPAC AF: 0.845 AC: 3257

ESP6500AA AF: 0.773 AC: 2788

ESP6500EA AF: 0.844 AC: 6866

ExAC AF: 0.746 AC: 90038

Asia WGS AF: 0.548 AC: 1907 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

May 23, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.2
DANN	Benign	0.30
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.095	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.75
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.013
Sift	Benign	0.53	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.066
MPC		0.048
ClinPred		0.0024	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.039
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7177192; hg19: chr15-40898643; COSMIC: COSV61150583;