rs11855334

chr15-40622574-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144508.5(KNL1):c.2310C>T(p.Val770=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.569

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
KNL1	NM_144508.5	c.2310C>T	p.Val770=	synonymous_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5	c.2388C>T	p.Val796=	synonymous_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.2310C>T	p.Val770=	synonymous_variant	10/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59153 AN: 151824 Hom.: 11718 Cov.: 32

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

GnomAD3 exomes AF: 0.386 AC: 95679 AN: 247606 Hom.: 19427 AF XY: 0.399 AC XY: 53636 AN XY: 134404

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 SAS exome AF: 0.485

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.: 46 AF XY: 0.401 AC XY: 291157 AN XY: 726232

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.459

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.390 AC: 59204 AN: 151944 Hom.: 11733 Cov.: 32 AF XY: 0.392 AC XY: 29086 AN XY: 74256

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.374

Alfa AF: 0.398 Hom.: 24229

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

Primary Microcephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Microcephaly 4, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	5.3
Dann	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs11855334; hg19: chr15-40914772; COSMIC: COSV61150598; COSMIC: COSV61150598;