17-46066611-G-C

Variant names:

• chr17-46066611-G-C
• rs774841964
• NM_015443.4:c.1774C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_015443.4(KANSL1):​c.1774C>G​(p.Arg592Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R592Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 3 publications found

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]

KANSL1 Gene-Disease associations (from GenCC):

• Koolen-de Vries syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-46066610-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2505885.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.1774C>G	p.Arg592Gly	missense_variant	Exon 6 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.1774C>G	p.Arg592Gly	missense_variant	Exon 6 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 18, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R592G variant in the KANSL1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R592G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R592G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R592G as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
PhyloP100		4.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.6	D;.;.;.;.;D;.;.;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;.;.;.;D;.;.;.;.
Sift4G	Uncertain	0.013	D;D;D;.;D;D;.;.;.;.
Vest4		0.98
MutPred		0.59		Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);Loss of MoRF binding (P = 0.0355);.;Loss of MoRF binding (P = 0.0355);
MVP		0.79
MPC		1.5
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.76
Mutation Taster		=10/90	disease causing

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: rs774841964; hg19: chr17-44143977;