chr17-46171482-G-A

Variant names:

• chr17-46171482-G-A
• rs17662853
• NM_015443.4:c.662C>T

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.662C>T​(p.Thr221Ile) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,608,748 control chromosomes in the GnomAD database, including 20,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T221A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1230 hom., cov: 35)
  • Exomes 𝑓: 0.16 (19569 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.54
• Publications: 35 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 (MetaRNN=9.5272064E-4).
• BP6: Variant 17-46171482-G-A is Benign according to our data. Variant chr17-46171482-G-A is described in ClinVar as Benign. ClinVar VariationId is 323791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 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.662C>T	p.Thr221Ile	missense	Exon 2 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.662C>T	p.Thr221Ile	missense	Exon 2 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.662C>T	p.Thr221Ile	missense	Exon 3 of 16	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.662C>T	p.Thr221Ile	missense	Exon 2 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.662C>T	p.Thr221Ile	missense	Exon 2 of 15	ENSP00000262419.6
	KANSL1	ENST00000572904.6	TSL:5	c.662C>T	p.Thr221Ile	missense	Exon 2 of 15	ENSP00000461484.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16280 AN: 151682 Hom.: 1230 Cov.: 35

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.0708

Gnomad ASJ AF: 0.0803

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.0916

GnomAD2 exomes AF: 0.117 AC: 29267 AN: 250096 AF XY: 0.119

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.155 AC: 226190 AN: 1456948 Hom.: 19569 Cov.: 50 AF XY: 0.153 AC XY: 110776 AN XY: 724644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0212 AC: 711 AN: 33476

American (AMR) AF: 0.0471 AC: 2102 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0799 AC: 2082 AN: 26042

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39700

South Asian (SAS) AF: 0.0991 AC: 8501 AN: 85762

European-Finnish (FIN) AF: 0.215 AC: 11470 AN: 53292

Middle Eastern (MID) AF: 0.0458 AC: 264 AN: 5768

European-Non Finnish (NFE) AF: 0.174 AC: 193099 AN: 1108018

Other (OTH) AF: 0.132 AC: 7939 AN: 60238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.107 AC: 16277 AN: 151800 Hom.: 1230 Cov.: 35 AF XY: 0.108 AC XY: 8041 AN XY: 74194

African (AFR) AF: 0.0258 AC: 1072 AN: 41510

American (AMR) AF: 0.0707 AC: 1080 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0803 AC: 278 AN: 3464

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.0829 AC: 399 AN: 4814

European-Finnish (FIN) AF: 0.218 AC: 2296 AN: 10520

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10663 AN: 67734

Other (OTH) AF: 0.0906 AC: 191 AN: 2108

Alfa AF: 0.129 Hom.: 2967

Bravo AF: 0.0940

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.172 AC: 662

ESP6500AA AF: 0.0322 AC: 142

ESP6500EA AF: 0.153 AC: 1314

ExAC AF: 0.123 AC: 14919

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Koolen-de Vries syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.00095	T
MetaSVM	Benign	-0.95	T
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.094
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.17	T
Vest4		0.53
MPC		0.099
ClinPred		0.020	T
GERP RS		3.3
PromoterAI		-0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.26
Mutation Taster		=298/2	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: rs17662853; hg19: chr17-44248848; COSMIC: COSV52266840; COSMIC: COSV52266840;