NM_001348716.2:c.780_791dupACCACCACCACC

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_001348716.2(KDM6B):c.780_791dupACCACCACCACC(p.Pro261_Pro264dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,097,236 control chromosomes in the GnomAD database, including 9 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0019 ( 9 hom. )

Failed GnomAD Quality Control

Consequence

KDM6B
NM_001348716.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.250

Publications

8 publications found

Variant links:

Genes affected

KDM6B (HGNC:29012): (lysine demethylase 6B) The protein encoded by this gene is a lysine-specific demethylase that specifically demethylates di- or tri-methylated lysine 27 of histone H3 (H3K27me2 or H3K27me3). H3K27 trimethylation is a repressive epigenetic mark controlling chromatin organization and gene silencing. This protein can also demethylate non-histone proteins such as retinoblastoma protein. Through its demethylation actvity this gene influences cellular differentiation and development, tumorigenesis, inflammatory diseases, and neurodegenerative diseases. This protein has two classical nuclear localization signals at its N-terminus. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

KDM6B Gene-Disease associations (from GenCC):

syndromic intellectual disability
Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

KDM6B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001348716.2

BP6

Variant 17-7846859-T-TACCACCACCACC is Benign according to our data. Variant chr17-7846859-T-TACCACCACCACC is described in ClinVar as Likely_benign. ClinVar VariationId is 3037897.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6B	NM_001348716.2 link	c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2 link	c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDM6B	ENST00000448097.7 link	c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	5	NM_001348716.2	ENSP00000412513.2	O15054-2
KDM6B	ENST00000254846.9 link	c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22	1		ENSP00000254846.5	O15054-1
KDM6B	ENST00000570632.1 link	c.711+147_711+158dupACCACCACCACC		intron_variant	Intron 7 of 8	5		ENSP00000458445.1	I3L0Z0

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

271

AN:

118286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00214

Gnomad ASJ

AF:

0.00481

Gnomad EAS

AF:

0.00787

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00167

Gnomad OTH

AF:

0.000661

GnomAD4 exome

AF:

0.00188

AC:

2062

AN:

1097236

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1009

AN XY:

554504

show subpopulations

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

African (AFR)

AF:

0.00313

AC:

AN:

25578

American (AMR)

AF:

0.00171

AC:

AN:

38600

Ashkenazi Jewish (ASJ)

AF:

0.00407

AC:

AN:

22352

East Asian (EAS)

AF:

0.00907

AC:

323

AN:

35624

South Asian (SAS)

AF:

0.00118

AC:

AN:

75528

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

35930

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

3566

European-Non Finnish (NFE)

AF:

0.00157

AC:

1271

AN:

812110

Other (OTH)

AF:

0.00209

AC:

100

AN:

47948

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00230

AC:

272

AN:

118348

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

117

AN XY:

55506

show subpopulations

African (AFR)

AF:

0.00314

AC:

AN:

29014

American (AMR)

AF:

0.00214

AC:

AN:

11682

Ashkenazi Jewish (ASJ)

AF:

0.00481

AC:

AN:

3118

East Asian (EAS)

AF:

0.00789

AC:

AN:

4180

South Asian (SAS)

AF:

0.000835

AC:

AN:

3594

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

6036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.00167

AC:

AN:

58164

Other (OTH)

AF:

0.000654

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00

Hom.:

2265

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KDM6B: BS1 -

KDM6B-related disorder

Benign:1

Oct 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.25

Mutation Taster

=89/11

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over