rs8030491

chr15-40610853-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000346991.9(KNL1):c.305G>A(p.Arg102Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 454,554 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (131 hom., cov: 32)
  • Exomes 𝑓: 0.016 (81 hom.)
• Consequence: KNL1 ENST00000346991.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00364846).
• BP6: Variant 15-40610853-G-A is Benign according to our data. Variant chr15-40610853-G-A is described in ClinVar as [Benign]. Clinvar id is 128580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.250+556G>A		intron_variant		ENST00000399668.7
KNL1	NM_170589.5	c.305G>A	p.Arg102Gln	missense_variant	7/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.250+556G>A		intron_variant		1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4775 AN: 152034 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0264

GnomAD3 exomes AF: 0.0155 AC: 1981 AN: 127888 Hom.: 40 AF XY: 0.0153 AC XY: 1075 AN XY: 70050

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.00912

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000192

Gnomad SAS exome AF: 0.00952

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0160 AC: 4843 AN: 302402 Hom.: 81 Cov.: 0 AF XY: 0.0156 AC XY: 2686 AN XY: 172296

Gnomad4 AFR exome AF: 0.0684

Gnomad4 AMR exome AF: 0.00928

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.00965

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0168

GnomAD4 genome AF: 0.0314 AC: 4782 AN: 152152 Hom.: 131 Cov.: 32 AF XY: 0.0312 AC XY: 2318 AN XY: 74370

Gnomad4 AFR AF: 0.0725

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00955

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0269 Hom.: 12

Bravo AF: 0.0319

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0125 AC: 48

ExAC AF: 0.0122 AC: 171

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Mar 24, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.10
Dann	Benign	0.71
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.042
Sift	Benign	0.34	T
Sift4G	Benign	0.55	T
Polyphen		0.19	B
Vest4		0.048
MPC		0.041
ClinPred		0.0061	T
GERP RS		-0.85
Varity_R		0.045
gMVP		0.052

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8030491; hg19: chr15-40903051; COSMIC: COSV61151110; COSMIC: COSV61151110;