rs2412541

Variant names:

• chr15-40621642-G-T
• rs2412541
• NM_144508.5:c.1378G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144508.5(KNL1):​c.1378G>T​(p.Ala460Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,610,978 control chromosomes in the GnomAD database, including 536,825 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47836 hom., cov: 33)
  • Exomes 𝑓: 0.81 (488989 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.131
• Publications: 55 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.9927845E-7).
• BP6: Variant 15-40621642-G-T is Benign according to our data. Variant chr15-40621642-G-T is described in ClinVar as Benign. ClinVar VariationId is 128588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.845 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.1378G>T	p.Ala460Ser	missense	Exon 10 of 26	NP_653091.3
	KNL1	NM_170589.5		c.1456G>T	p.Ala486Ser	missense	Exon 11 of 27	NP_733468.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.1378G>T	p.Ala460Ser	missense	Exon 10 of 26	ENSP00000382576.3
	KNL1	ENST00000346991.9	TSL:1	c.1456G>T	p.Ala486Ser	missense	Exon 11 of 27	ENSP00000335463.6
	KNL1	ENST00000533001.1	TSL:1	n.1523G>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119324 AN: 152036 Hom.: 47798 Cov.: 33

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.775

GnomAD2 exomes AF: 0.737 AC: 182152 AN: 247282 AF XY: 0.752

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.809

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.842

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.784

GnomAD4 exome AF: 0.811 AC: 1183464 AN: 1458824 Hom.: 488989 Cov.: 43 AF XY: 0.812 AC XY: 589256 AN XY: 725744

African (AFR) AF: 0.771 AC: 25691 AN: 33336

American (AMR) AF: 0.510 AC: 22632 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 21000 AN: 25990

East Asian (EAS) AF: 0.310 AC: 12281 AN: 39650

South Asian (SAS) AF: 0.763 AC: 65604 AN: 86008

European-Finnish (FIN) AF: 0.836 AC: 44577 AN: 53348

Middle Eastern (MID) AF: 0.824 AC: 4734 AN: 5746

European-Non Finnish (NFE) AF: 0.846 AC: 938931 AN: 1110170

Other (OTH) AF: 0.797 AC: 48014 AN: 60236

GnomAD4 genome AF: 0.785 AC: 119405 AN: 152154 Hom.: 47836 Cov.: 33 AF XY: 0.779 AC XY: 57980 AN XY: 74390

African (AFR) AF: 0.770 AC: 31946 AN: 41512

American (AMR) AF: 0.659 AC: 10073 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2797 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1671 AN: 5154

South Asian (SAS) AF: 0.727 AC: 3505 AN: 4822

European-Finnish (FIN) AF: 0.846 AC: 8959 AN: 10588

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

European-Non Finnish (NFE) AF: 0.851 AC: 57876 AN: 68004

Other (OTH) AF: 0.775 AC: 1637 AN: 2112

Alfa AF: 0.818 Hom.: 181732

Bravo AF: 0.761

TwinsUK AF: 0.850 AC: 3150

ALSPAC AF: 0.845 AC: 3256

ESP6500AA AF: 0.773 AC: 2830

ESP6500EA AF: 0.844 AC: 6881

ExAC AF: 0.745 AC: 90022

Asia WGS AF: 0.548 AC: 1905 AN: 3476

EpiCase AF: 0.843

EpiControl AF: 0.842

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephaly 4, primary, autosomal recessive (1)
-	-	1	not specified (1)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.3
DANN	Benign	0.19
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.13
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.035
ClinPred		0.0014	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.071
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2412541; hg19: chr15-40913840; COSMIC: COSV61152671; COSMIC: COSV61152671;