15-40603242-T-C

Variant names:

• chr15-40603242-T-C
• rs12708401
• NM_144508.5:c.35+276T>C

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.35+276T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.785 in 152,098 control chromosomes in the GnomAD database, including 47,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.78 (47853 hom., cov: 31)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-1.02).
• BP6: Variant 15-40603242-T-C is Benign according to our data. Variant chr15-40603242-T-C is described in ClinVar as [Benign]. Clinvar id is 1269384.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.35+276T>C		intron_variant	Intron 2 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.35+276T>C		intron_variant	Intron 2 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.35+276T>C		intron_variant	Intron 2 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119305 AN: 151980 Hom.: 47815 Cov.: 31

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.785 AC: 119386 AN: 152098 Hom.: 47853 Cov.: 31 AF XY: 0.780 AC XY: 57982 AN XY: 74360

African (AFR) AF: 0.770 AC: 31907 AN: 41454

American (AMR) AF: 0.659 AC: 10059 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2806 AN: 3472

East Asian (EAS) AF: 0.324 AC: 1673 AN: 5158

South Asian (SAS) AF: 0.727 AC: 3502 AN: 4820

European-Finnish (FIN) AF: 0.847 AC: 8974 AN: 10598

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57891 AN: 68010

Other (OTH) AF: 0.776 AC: 1635 AN: 2108

Alfa AF: 0.825 Hom.: 6766

Bravo AF: 0.761

Asia WGS AF: 0.548 AC: 1908 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.56
DANN	Benign	0.28
PhyloP100		-1.0
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: rs12708401; hg19: chr15-40895440;