Genetic Variant KDM6B:p.Pro261_Pro264dup (chr17-7846859-T-TACCACCACCACC) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

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. Variant has been reported in ClinVar as Likely benign (no stars).

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 no assertion criteria provided B:1

Conservation

PhyloP100: 0.250

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

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 id is 3037897.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00188 (2062/1097236) while in subpopulation EAS AF= 0.00907 (323/35624). AF 95% confidence interval is 0.00825. There are 9 homozygotes in gnomad4_exome. There are 1009 alleles in male gnomad4_exome subpopulation. Median coverage is 43. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 2062 AD 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:

0.00

AC:

271

AN:

118286

Hom.:

Cov.:

FAILED QC

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

Gnomad4 AFR exome

AF:

0.00313

Gnomad4 AMR exome

AF:

0.00171

Gnomad4 ASJ exome

AF:

0.00407

Gnomad4 EAS exome

AF:

0.00907

Gnomad4 SAS exome

AF:

0.00118

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.00157

Gnomad4 OTH exome

AF:

0.00209

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

Gnomad4 AFR

AF:

0.00314

Gnomad4 AMR

AF:

0.00214

Gnomad4 ASJ

AF:

0.00481

Gnomad4 EAS

AF:

0.00789

Gnomad4 SAS

AF:

0.000835

Gnomad4 FIN

AF:

0.00116

Gnomad4 NFE

AF:

0.00167

Gnomad4 OTH

AF:

0.000654

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over