17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001348716.2(KDM6B):c.786_791dup(p.Pro263_Pro264dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (34367 hom., cov: 0)
  • Exomes 𝑓: 0.56 (124679 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 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 Benign. Variant got -8 ACMG points.

• BP6: Variant 17-7846859-T-TACCACC is Benign according to our data. Variant chr17-7846859-T-TACCACC is described in ClinVar as [Likely_benign]. Clinvar id is 254122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6B	NM_001348716.2	c.786_791dup	p.Pro263_Pro264dup	inframe_insertion	10/24	ENST00000448097.7
KDM6B	NM_001080424.2	c.786_791dup	p.Pro263_Pro264dup	inframe_insertion	9/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6B	ENST00000448097.7	c.786_791dup	p.Pro263_Pro264dup	inframe_insertion	10/24	5	NM_001348716.2	A2
KDM6B	ENST00000254846.9	c.786_791dup	p.Pro263_Pro264dup	inframe_insertion	9/22	1		P2
KDM6B	ENST00000570632.1	c.711+153_711+158dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 89411 AN: 117718 Hom.: 34351 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.722

Gnomad MID AF: 0.895

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.771

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.565 AC: 614608 AN: 1088244 Hom.: 124679 Cov.: 43 AF XY: 0.559 AC XY: 307306 AN XY: 549990

Gnomad4 AFR exome AF: 0.549

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.415

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.591

Gnomad4 OTH exome AF: 0.547

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.760 AC: 89456 AN: 117782 Hom.: 34367 Cov.: 0 AF XY: 0.750 AC XY: 41431 AN XY: 55212

Gnomad4 AFR AF: 0.758

Gnomad4 AMR AF: 0.676

Gnomad4 ASJ AF: 0.801

Gnomad4 EAS AF: 0.574

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.722

Gnomad4 NFE AF: 0.796

Gnomad4 OTH AF: 0.773

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 77.92% (rs779500270, 8811/11110 alleles, 3564 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -

Oromandibular-limb hypogenesis spectrum Uncertain:1

Uncertain significance, no assertion criteria provided

research

CHU Sainte-Justine Research Center, University of Montreal

Aug 12, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2021

This variant is associated with the following publications: (PMID: 33337535) -

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;