17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACC

Variant names:

• chr17-7846859-T-TACC
• rs61462443
• NM_001348716.2:c.789_791dupACC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_001348716.2(KDM6B):​c.789_791dupACC​(p.Pro264dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (247 hom., cov: 0)
  • Exomes 𝑓: 0.057 (360 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.250
• Publications: 8 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001348716.2
• BP6: Variant 17-7846859-T-TACC is Benign according to our data. Variant chr17-7846859-T-TACC is described in ClinVar as Benign. ClinVar VariationId is 1206219.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6B	NM_001348716.2	c.789_791dupACC	p.Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.789_791dupACC	p.Pro264dup	disruptive_inframe_insertion	Exon 9 of 22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.789_791dupACC	p.Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.789_791dupACC	p.Pro264dup	disruptive_inframe_insertion	Exon 9 of 22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.711+156_711+158dupACC		intron_variant	Intron 7 of 8	5		ENSP00000458445.1

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 5127 AN: 118086 Hom.: 246 Cov.: 0

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.0206

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0219

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0471

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0573 AC: 51094 AN: 891990 Hom.: 360 Cov.: 43 AF XY: 0.0568 AC XY: 25357 AN XY: 446458

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

African (AFR) AF: 0.132 AC: 2517 AN: 19056

American (AMR) AF: 0.0277 AC: 834 AN: 30150

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 1273 AN: 16306

East Asian (EAS) AF: 0.00645 AC: 193 AN: 29932

South Asian (SAS) AF: 0.0420 AC: 2403 AN: 57184

European-Finnish (FIN) AF: 0.0412 AC: 1121 AN: 27238

Middle Eastern (MID) AF: 0.0560 AC: 145 AN: 2588

European-Non Finnish (NFE) AF: 0.0601 AC: 40383 AN: 671744

Other (OTH) AF: 0.0589 AC: 2225 AN: 37792

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0434 AC: 5129 AN: 118142 Hom.: 247 Cov.: 0 AF XY: 0.0426 AC XY: 2360 AN XY: 55388

African (AFR) AF: 0.0917 AC: 2659 AN: 28984

American (AMR) AF: 0.0252 AC: 294 AN: 11656

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 142 AN: 3118

East Asian (EAS) AF: 0.00574 AC: 24 AN: 4180

South Asian (SAS) AF: 0.0248 AC: 89 AN: 3588

European-Finnish (FIN) AF: 0.0313 AC: 186 AN: 5952

Middle Eastern (MID) AF: 0.0120 AC: 3 AN: 250

European-Non Finnish (NFE) AF: 0.0283 AC: 1645 AN: 58114

Other (OTH) AF: 0.0466 AC: 71 AN: 1522

Alfa AF: 0.178 Hom.: 2265

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

KDM6B-related disorder Benign:1

Jun 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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 (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61462443; hg19: chr17-7750177; COSMIC: COSV54682108; COSMIC: COSV54682108;