chr17-46050683-G-A

Variant names:

• chr17-46050683-G-A
• rs368180304
• NM_015443.4:c.1870C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_015443.4(KANSL1):​c.1870C>T​(p.Arg624Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R624H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79
• Publications: 1 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000394 (6/152168) while in subpopulation NFE AF = 0.0000588 (4/68036). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	NM_015443.4	MANE Select	c.1870C>T	p.Arg624Cys	missense	Exon 7 of 15	NP_056258.1	Q7Z3B3-1
	KANSL1	NM_001193466.2		c.1870C>T	p.Arg624Cys	missense	Exon 7 of 15	NP_001180395.1	Q7Z3B3-1
	KANSL1	NM_001379198.1		c.1870C>T	p.Arg624Cys	missense	Exon 8 of 16	NP_001366127.1	Q7Z3B3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1870C>T	p.Arg624Cys	missense	Exon 7 of 15	ENSP00000387393.3	Q7Z3B3-1
	KANSL1	ENST00000262419.10	TSL:1	c.1870C>T	p.Arg624Cys	missense	Exon 7 of 15	ENSP00000262419.6	Q7Z3B3-1
	KANSL1	ENST00000918919.1		c.1870C>T	p.Arg624Cys	missense	Exon 7 of 16	ENSP00000588978.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000480 AC: 12 AN: 250244 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461348 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 726934

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86194

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53402

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111664

Other (OTH) AF: 0.0000497 AC: 3 AN: 60358

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

African (AFR) AF: 0.0000483 AC: 2 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Koolen-de Vries syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.2	T
PhyloP100		6.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.086	T
Vest4		0.80
MVP		0.56
MPC		1.6
ClinPred		0.68	D
GERP RS		6.1
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.25
Mutation Taster		=71/29	polymorphism

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: rs368180304; hg19: chr17-44128049; COSMIC: COSV52268159; COSMIC: COSV52268159;