Genetic Variant KDM6B:p.Pro259_Pro264dup (chr17-7846859-T-TACCACCACCACCACCACC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001348716.2(KDM6B):c.774_791dupACCACCACCACCACCACC(p.Pro259_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 0.0000823 in 1,215,804 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

KDM6B
NM_001348716.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.250

Publications

0 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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001348716.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6B	NM_001348716.2 link	c.774_791dupACCACCACCACCACCACC	p.Pro259_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2 link	c.774_791dupACCACCACCACCACCACC	p.Pro259_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.774_791dupACCACCACCACCACCACC	p.Pro259_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	5	NM_001348716.2	ENSP00000412513.2	O15054-2
KDM6B	ENST00000254846.9 link	c.774_791dupACCACCACCACCACCACC	p.Pro259_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22	1		ENSP00000254846.5	O15054-1
KDM6B	ENST00000570632.1 link	c.711+141_711+158dupACCACCACCACCACCACC		intron_variant	Intron 7 of 8	5		ENSP00000458445.1	I3L0Z0

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

118294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000857

Gnomad ASJ

AF:

0.000321

Gnomad EAS

AF:

0.000238

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000661

GnomAD4 exome

AF:

0.0000784

AC:

AN:

1097510

Hom.:

Cov.:

AF XY:

0.0000775

AC XY:

AN XY:

554642

show subpopulations

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

African (AFR)

AF:

0.000195

AC:

AN:

25586

American (AMR)

AF:

0.000130

AC:

AN:

38604

Ashkenazi Jewish (ASJ)

AF:

0.000179

AC:

AN:

22352

East Asian (EAS)

AF:

0.0000561

AC:

AN:

35632

South Asian (SAS)

AF:

0.0000397

AC:

AN:

75536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3566

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

812346

Other (OTH)

AF:

0.000125

AC:

AN:

47958

⚠️ 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: 0.387

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000118

AC:

AN:

118294

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

55440

show subpopulations

African (AFR)

AF:

0.000138

AC:

AN:

28924

American (AMR)

AF:

0.0000857

AC:

AN:

11668

Ashkenazi Jewish (ASJ)

AF:

0.000321

AC:

AN:

3118

East Asian (EAS)

AF:

0.000238

AC:

AN:

4194

South Asian (SAS)

AF:

0.00

AC:

AN:

3612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

58174

Other (OTH)

AF:

0.000661

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

ClinVar

Not reported in ClinVar

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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17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACCACCACCACCACCACC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over