17-46066848-T-C

Variant names:

• chr17-46066848-T-C
• rs2301732
• NM_015443.4:c.1653-116A>G

Variant summary

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

The NM_015443.4(KANSL1):​c.1653-116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 712,794 control chromosomes in the GnomAD database, including 5,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (902 hom., cov: 32)
  • Exomes 𝑓: 0.054 (4646 hom.)
• Consequence: KANSL1 NM_015443.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.158
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-46066848-T-C is Benign according to our data. Variant chr17-46066848-T-C is described in ClinVar as Benign. ClinVar VariationId is 674896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	NM_015443.4	MANE Select	c.1653-116A>G		intron	N/A	NP_056258.1
	KANSL1	NM_001193466.2		c.1653-116A>G		intron	N/A	NP_001180395.1
	KANSL1	NM_001379198.1		c.1653-116A>G		intron	N/A	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1653-116A>G		intron	N/A	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.1653-116A>G		intron	N/A	ENSP00000262419.6
	KANSL1	ENST00000572904.6	TSL:5	c.1653-116A>G		intron	N/A	ENSP00000461484.1

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7202 AN: 152168 Hom.: 893 Cov.: 32

Gnomad AFR AF: 0.00690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.0721

Gnomad FIN AF: 0.0782

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00956

Gnomad OTH AF: 0.0441

GnomAD4 exome AF: 0.0541 AC: 30340 AN: 560508 Hom.: 4646 AF XY: 0.0534 AC XY: 15521 AN XY: 290676

African (AFR) AF: 0.00602 AC: 88 AN: 14630

American (AMR) AF: 0.251 AC: 4943 AN: 19708

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 392 AN: 14476

East Asian (EAS) AF: 0.470 AC: 14938 AN: 31784

South Asian (SAS) AF: 0.0596 AC: 2783 AN: 46656

European-Finnish (FIN) AF: 0.0739 AC: 2295 AN: 31074

Middle Eastern (MID) AF: 0.0152 AC: 38 AN: 2498

European-Non Finnish (NFE) AF: 0.00887 AC: 3281 AN: 370058

Other (OTH) AF: 0.0534 AC: 1582 AN: 29624

GnomAD4 genome AF: 0.0474 AC: 7223 AN: 152286 Hom.: 902 Cov.: 32 AF XY: 0.0544 AC XY: 4054 AN XY: 74462

African (AFR) AF: 0.00688 AC: 286 AN: 41576

American (AMR) AF: 0.179 AC: 2730 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.421 AC: 2177 AN: 5170

South Asian (SAS) AF: 0.0719 AC: 347 AN: 4824

European-Finnish (FIN) AF: 0.0782 AC: 830 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00957 AC: 651 AN: 68016

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0390 Hom.: 108

Bravo AF: 0.0597

Asia WGS AF: 0.193 AC: 670 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.58
DANN	Benign	0.73
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs2301732; hg19: chr17-44144214; COSMIC: COSV52267665;