17-46171334-CAG-C

Position:

• chr17-46171334-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_015443.4(KANSL1):​c.808_809del​(p.Leu270ValfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KANSL1 NM_015443.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:2
• Conservation: PhyloP100: 2.03

Genes affected

KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-46171334-CAG-C is Pathogenic according to our data. Variant chr17-46171334-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46171334-CAG-C is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.808_809del	p.Leu270ValfsTer11	frameshift_variant	2/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.808_809del	p.Leu270ValfsTer11	frameshift_variant	2/15	1	NM_015443.4	ENSP00000387393	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251458 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461878 Hom.: 0 AF XY: 0.0000206 AC XY: 15 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 35 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Koolen-de Vries syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 28, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2022	- -
Uncertain significance, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Jun 23, 2022	The variant c.808_809del (p.Leu270Valfs*11) in the KANSL1 gene is reported with conflicting interpretations (pathogenic, likely pathogenic, uncertain) in ClinVar for Koolen-de Vries syndrome (Variation ID: 168412) and as likely pathogenic in the LOVD database v.3.0 (genomic variant: #0000795640). The variant c.808_809del (p.Leu270Valfs*11) has been reported as pathogenic by Niar et al. (2018, PMID: 30293248) in a patient with a diagnosis of Koolen-deVries syndrome, which had developmental delay, intellectual disability, hypotony, ptosis, short stature, and ligamentous laxity. The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 11 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.00002386 in gnomAD exomes and di 0.00003185 in gnomAD genomes with no homozygous individuals reported. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.808_809delCT (p.L270Vfs*11) alteration, located in exon 2 (coding exon 1) of the KANSL1 gene, consists of a deletion of 2 nucleotides from position 808 to 809, causing a translational frameshift with a predicted alternate stop codon after 11 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.808_809delCT allele has an overall frequency of 0.002% (7/282852) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. Loss of function alterations in this region of the KANSL1 gene are more common in population databases than expected for likely pathogenic/disease-causing variants (Koolen, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

KANSL1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

The KANSL1 c.808_809delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu270Valfs*11). This variant was reported in multiple individuals with Koolen-de Vries syndrome or a neurodevelopmental phenotype. In many cases, the variant arose de novo (Nair et al. 2018. PubMed ID: 30293248; Table S1 - Gabriel et al. 2021. PubMed ID: 34958143; Tolusso et al. 2021. PubMed ID: 33442022; Table S2 - Turner et al. 2019. PubMed ID: 31785789). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-44248700-CAG-C). Frameshift variants in KANSL1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs551541795; hg19: chr17-44248700;