15-40608876-C-T

Position:

• chr15-40608876-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_144508.5(KNL1):​c.165C>T​(p.Asn55=) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.541

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 -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: {Benign=1, Likely_benign=2, Uncertain_significance=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	UniProt
KNL1	NM_144508.5	c.165C>T	p.Asn55=	synonymous_variant	5/26	ENST00000399668.7
KNL1	NM_170589.5	c.165C>T	p.Asn55=	synonymous_variant	5/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.165C>T	p.Asn55=	synonymous_variant	5/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152004 Hom.: 1 Cov.: 30

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.: 1 AF XY: 0.00238 AC XY: 320 AN XY: 134682

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.: 9 Cov.: 29 AF XY: 0.00205 AC XY: 1485 AN XY: 725710

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.: 1 Cov.: 30 AF XY: 0.00130 AC XY: 97 AN XY: 74358

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.: 1

Bravo AF: 0.00130

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	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

Other links and lift over

dbSNP: rs201818761; hg19: chr15-40901074;