ENST00000346991.9:c.305G>A

Variant names:

• chr15-40610853-G-A
• rs8030491
• ENST00000346991.9:c.305G>A

Variant summary

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

The ENST00000346991.9(KNL1):​c.305G>A​(p.Arg102Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 454,554 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (131 hom., cov: 32)
  • Exomes 𝑓: 0.016 (81 hom.)
• Consequence: KNL1 ENST00000346991.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.22
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00364846).
• BP6: Variant 15-40610853-G-A is Benign according to our data. Variant chr15-40610853-G-A is described in ClinVar as Benign. ClinVar VariationId is 128580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000346991.9. 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.250+556G>A		intron	N/A	NP_653091.3
	KNL1	NM_170589.5		c.305G>A	p.Arg102Gln	missense	Exon 7 of 27	NP_733468.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000346991.9	TSL:1	c.305G>A	p.Arg102Gln	missense	Exon 7 of 27	ENSP00000335463.6
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.250+556G>A		intron	N/A	ENSP00000382576.3
	KNL1	ENST00000533001.1	TSL:1	n.395+556G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4775 AN: 152034 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0264

GnomAD2 exomes AF: 0.0155 AC: 1981 AN: 127888 AF XY: 0.0153

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.00912

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0160 AC: 4843 AN: 302402 Hom.: 81 Cov.: 0 AF XY: 0.0156 AC XY: 2686 AN XY: 172296

African (AFR) AF: 0.0684 AC: 586 AN: 8568

American (AMR) AF: 0.00928 AC: 253 AN: 27270

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 261 AN: 10778

East Asian (EAS) AF: 0.000109 AC: 1 AN: 9192

South Asian (SAS) AF: 0.00965 AC: 576 AN: 59678

European-Finnish (FIN) AF: 0.0121 AC: 149 AN: 12362

Middle Eastern (MID) AF: 0.0219 AC: 39 AN: 1778

European-Non Finnish (NFE) AF: 0.0173 AC: 2742 AN: 158690

Other (OTH) AF: 0.0168 AC: 236 AN: 14086

GnomAD4 genome AF: 0.0314 AC: 4782 AN: 152152 Hom.: 131 Cov.: 32 AF XY: 0.0312 AC XY: 2318 AN XY: 74370

African (AFR) AF: 0.0725 AC: 3008 AN: 41502

American (AMR) AF: 0.0146 AC: 223 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00955 AC: 46 AN: 4818

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1152 AN: 67998

Other (OTH) AF: 0.0261 AC: 55 AN: 2108

Alfa AF: 0.0282 Hom.: 13

Bravo AF: 0.0319

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0125 AC: 48

ExAC AF: 0.0122 AC: 171

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.10
DANN	Benign	0.71
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.94	T
PhyloP100		-1.2
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.042
Sift	Benign	0.34	T
Sift4G	Benign	0.55	T
Polyphen		0.19	B
Vest4		0.048
MPC		0.041
ClinPred		0.0061	T
GERP RS		-0.85
Varity_R		0.045
gMVP		0.052
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8030491; hg19: chr15-40903051; COSMIC: COSV61151110;