chr15-40651905-C-T

Position:

• chr15-40651905-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_144508.5(KNL1):​c.6315-100C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 681,090 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (60 hom., cov: 32)
  • Exomes 𝑓: 0.029 (305 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.024 (3657/152230) while in subpopulation NFE AF= 0.0369 (2509/68022). AF 95% confidence interval is 0.0357. There are 60 homozygotes in gnomad4. There are 1750 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5	c.6315-100C>T		intron_variant		ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.6393-100C>T		intron_variant			NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.6315-100C>T		intron_variant		1	NM_144508.5	ENSP00000382576.3
KNL1	ENST00000346991.9	c.6393-100C>T		intron_variant		1		ENSP00000335463.6
KNL1	ENST00000526913.5	n.3447-100C>T		intron_variant		1		ENSP00000432565.1
KNL1	ENST00000532347.1	n.395-100C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3656 AN: 152114 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00609

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.0294 AC: 15533 AN: 528860 Hom.: 305 AF XY: 0.0284 AC XY: 7898 AN XY: 278418

Gnomad4 AFR exome AF: 0.00510

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0395

Gnomad4 EAS exome AF: 0.0000318

Gnomad4 SAS exome AF: 0.00493

Gnomad4 FIN exome AF: 0.0270

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0240 AC: 3657 AN: 152230 Hom.: 60 Cov.: 32 AF XY: 0.0235 AC XY: 1750 AN XY: 74448

Gnomad4 AFR AF: 0.00605

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.0302

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0273

Gnomad4 NFE AF: 0.0369

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0292 Hom.: 56

Bravo AF: 0.0239

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.74

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: rs3092980; hg19: chr15-40944103;