dbSNP rs138698439: KANSL1:p.Ser609Asn (chr17-46066559-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015443.4(KANSL1):c.1826G>A(p.Ser609Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,613,310 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.225

Publications

3 publications found

Variant links:

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

KANSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049020946).

BP6

Variant 17-46066559-C-T is Benign according to our data. Variant chr17-46066559-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376914.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00142 (217/152320) while in subpopulation AFR AF = 0.00436 (181/41558). AF 95% confidence interval is 0.00384. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 217 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KANSL1	NM_015443.4	MANE Select	c.1826G>A	p.Ser609Asn	missense	Exon 6 of 15	NP_056258.1	Q7Z3B3-1
KANSL1	NM_001193466.2		c.1826G>A	p.Ser609Asn	missense	Exon 6 of 15	NP_001180395.1	Q7Z3B3-1
KANSL1	NM_001379198.1		c.1826G>A	p.Ser609Asn	missense	Exon 7 of 16	NP_001366127.1	Q7Z3B3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1826G>A	p.Ser609Asn	missense	Exon 6 of 15	ENSP00000387393.3	Q7Z3B3-1
KANSL1	ENST00000262419.10	TSL:1	c.1826G>A	p.Ser609Asn	missense	Exon 6 of 15	ENSP00000262419.6	Q7Z3B3-1
KANSL1	ENST00000918919.1		c.1826G>A	p.Ser609Asn	missense	Exon 6 of 16	ENSP00000588978.1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.000162

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000483

AC:

121

AN:

250312

AF XY:

0.000348

show subpopulations

Gnomad AFR exome

AF:

0.00474

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.000270

AC:

394

AN:

1460990

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

726752

show subpopulations

African (AFR)

AF:

0.00496

AC:

166

AN:

33460

American (AMR)

AF:

0.000761

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00125

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.000122

AC:

136

AN:

1111512

Other (OTH)

AF:

0.000795

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00142

AC:

217

AN:

152320

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00436

AC:

181

AN:

41558

American (AMR)

AF:

0.00118

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68036

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000664

Hom.:

Bravo

AF:

0.00187

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000328

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Koolen-de Vries syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.076

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

M_CAP

Benign

0.0070

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.93

PhyloP100

0.23

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.80

REVEL

Benign

0.025

Sift

Benign

0.052

Sift4G

Benign

0.40

Vest4

0.16

MVP

0.24

MPC

0.44

ClinPred

0.0078

GERP RS

4.0

gMVP

0.22

Mutation Taster

=282/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over