rs74970544

Variant names:

• chr15-40647014-A-G
• rs74970544
• NM_144508.5:c.6034A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144508.5(KNL1):​c.6034A>G​(p.Ile2012Val) variant causes a missense change. The variant allele was found at a frequency of 0.000677 in 1,507,072 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.50
• Publications: 1 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

ENSG00000259254 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00562194).
• BP6: Variant 15-40647014-A-G is Benign according to our data. Variant chr15-40647014-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00378 (576/152298) while in subpopulation AFR AF = 0.0133 (553/41562). AF 95% confidence interval is 0.0124. There are 3 homozygotes in GnomAd4. There are 280 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.6034A>G	p.Ile2012Val	missense	Exon 17 of 26	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.6112A>G	p.Ile2038Val	missense	Exon 18 of 27	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.6034A>G	p.Ile2012Val	missense	Exon 17 of 26	ENSP00000382576.3	Q8NG31-2
	KNL1	ENST00000346991.9	TSL:1	c.6112A>G	p.Ile2038Val	missense	Exon 18 of 27	ENSP00000335463.6	Q8NG31-1
	KNL1	ENST00000526913.5	TSL:1	n.3166A>G		non_coding_transcript_exon	Exon 8 of 18	ENSP00000432565.1	H0YCZ2

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152180 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000871 AC: 217 AN: 249030 AF XY: 0.000681

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000328 AC: 444 AN: 1354774 Hom.: 2 Cov.: 21 AF XY: 0.000266 AC XY: 181 AN XY: 679806

African (AFR) AF: 0.0122 AC: 380 AN: 31252

American (AMR) AF: 0.000563 AC: 25 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 83954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5558

European-Non Finnish (NFE) AF: 0.00000690 AC: 7 AN: 1015022

Other (OTH) AF: 0.000547 AC: 31 AN: 56724

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152298 Hom.: 3 Cov.: 31 AF XY: 0.00376 AC XY: 280 AN XY: 74476

African (AFR) AF: 0.0133 AC: 553 AN: 41562

American (AMR) AF: 0.00111 AC: 17 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00137 Hom.: 3

Bravo AF: 0.00394

ESP6500AA AF: 0.0133 AC: 48

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.075
Sift	Benign	0.098	T
Sift4G	Benign	0.26	T
Polyphen		0.0080	B
Vest4		0.44
MVP		0.26
MPC		0.071
ClinPred		0.010	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.080
Mutation Taster		=100/0	polymorphism

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: rs74970544; hg19: chr15-40939212;