15-40608876-C-T

Variant names:

• chr15-40608876-C-T
• rs201818761
• NM_144508.5:c.165C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_144508.5(KNL1):​c.165C>T​(p.Asn55Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,610,642 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: KNL1 NM_144508.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.541
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-40608876-C-T is Benign according to our data. Variant chr15-40608876-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 315843.
• BP7: Synonymous conserved (PhyloP=-0.541 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00139 (212/152122) while in subpopulation SAS AF = 0.00518 (25/4824). AF 95% confidence interval is 0.0036. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.165C>T	p.Asn55Asn	synonymous	Exon 5 of 26	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.165C>T	p.Asn55Asn	synonymous	Exon 5 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.165C>T	p.Asn55Asn	synonymous	Exon 5 of 26	ENSP00000382576.3	Q8NG31-2
	KNL1	ENST00000346991.9	TSL:1	c.165C>T	p.Asn55Asn	synonymous	Exon 5 of 27	ENSP00000335463.6	Q8NG31-1
	KNL1	ENST00000533001.1	TSL:1	n.310C>T		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152004 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00194 AC: 480 AN: 247464 AF XY: 0.00238

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00179 AC: 2612 AN: 1458520 Hom.: 9 Cov.: 29 AF XY: 0.00205 AC XY: 1485 AN XY: 725710

African (AFR) AF: 0.000688 AC: 23 AN: 33410

American (AMR) AF: 0.00143 AC: 64 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26086

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39624

South Asian (SAS) AF: 0.00658 AC: 567 AN: 86188

European-Finnish (FIN) AF: 0.000209 AC: 11 AN: 52650

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5762

European-Non Finnish (NFE) AF: 0.00159 AC: 1766 AN: 1109880

Other (OTH) AF: 0.00221 AC: 133 AN: 60246

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152122 Hom.: 1 Cov.: 30 AF XY: 0.00130 AC XY: 97 AN XY: 74358

African (AFR) AF: 0.000434 AC: 18 AN: 41510

American (AMR) AF: 0.00118 AC: 18 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10558

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 67996

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00134 Hom.: 1

Bravo AF: 0.00130

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00202

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.1
DANN	Benign	0.78
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism

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: rs201818761; hg19: chr15-40901074;