17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001348716.2(KDM6B):c.789_791dup(p.Pro263dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.250

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 17-7846859-T-TACC is Benign according to our data. Variant chr17-7846859-T-TACC is described in ClinVar as [Benign]. Clinvar id is 1206219.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6B	NM_001348716.2	c.789_791dup	p.Pro263dup	inframe_insertion	10/24	ENST00000448097.7
KDM6B	NM_001080424.2	c.789_791dup	p.Pro263dup	inframe_insertion	9/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6B	ENST00000448097.7	c.789_791dup	p.Pro263dup	inframe_insertion	10/24	5	NM_001348716.2	A2
KDM6B	ENST00000254846.9	c.789_791dup	p.Pro263dup	inframe_insertion	9/22	1		P2
KDM6B	ENST00000570632.1	c.711+156_711+158dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5127 AN: 118086 Hom.: 246 Cov.: 0 FAILED QC

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

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0781

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.0420

Gnomad4 FIN exome AF: 0.0412

Gnomad4 NFE exome AF: 0.0601

Gnomad4 OTH exome AF: 0.0589

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

Gnomad4 AFR AF: 0.0917

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0455

Gnomad4 EAS AF: 0.00574

Gnomad4 SAS AF: 0.0248

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0466

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

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KDM6B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

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). -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61462443; hg19: chr17-7750177;