rs12385982

Variant names:

• chr15-40602637-C-A
• rs12385982
• NM_144508.5:c.-17-278C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144508.5(KNL1):​c.-17-278C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 151,400 control chromosomes in the GnomAD database, including 11,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.38 (11458 hom., cov: 29)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.205
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-40602637-C-A is Benign according to our data. Variant chr15-40602637-C-A is described in ClinVar as Benign. ClinVar VariationId is 1235131.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.-17-278C>A		intron	N/A	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.-17-278C>A		intron	N/A	NP_733468.3	Q8NG31-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.-17-278C>A		intron	N/A	ENSP00000382576.3	Q8NG31-2
	KNL1	ENST00000346991.9	TSL:1	c.-17-278C>A		intron	N/A	ENSP00000335463.6	Q8NG31-1
	KNL1	ENST00000533001.1	TSL:1	n.129-278C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57540 AN: 151282 Hom.: 11461 Cov.: 29

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.0827

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.395

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.380 AC: 57546 AN: 151400 Hom.: 11458 Cov.: 29 AF XY: 0.373 AC XY: 27593 AN XY: 73974

African (AFR) AF: 0.350 AC: 14415 AN: 41244

American (AMR) AF: 0.325 AC: 4947 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1389 AN: 3468

East Asian (EAS) AF: 0.0821 AC: 422 AN: 5140

South Asian (SAS) AF: 0.266 AC: 1277 AN: 4798

European-Finnish (FIN) AF: 0.375 AC: 3924 AN: 10470

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29911 AN: 67766

Other (OTH) AF: 0.392 AC: 818 AN: 2088

Alfa AF: 0.395 Hom.: 1551

Bravo AF: 0.372

Asia WGS AF: 0.167 AC: 580 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.71
PhyloP100		0.20
Mutation Taster		=100/0	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: rs12385982; hg19: chr15-40894835;