Genetic Variant NM_001348716.2:c.771_791delACCACCACCACCACCACCACC (chr17-7846859-TACCACCACCACCACCACCACC-T) – 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.771_791delACCACCACCACCACCACCACC(p.Pro258_Pro264del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000111 in 1,215,894 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 DEL_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 0.000093 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KDM6B
NM_001348716.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

Publications

8 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:

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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.771_791delACCACCACCACCACCACCACC	p.Pro258_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2 link	c.771_791delACCACCACCACCACCACCACC	p.Pro258_Pro264del	disruptive_inframe_deletion	Exon 9 of 22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDM6B	ENST00000448097.7 link	c.771_791delACCACCACCACCACCACCACC	p.Pro258_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	5	NM_001348716.2	ENSP00000412513.2	O15054-2
KDM6B	ENST00000254846.9 link	c.771_791delACCACCACCACCACCACCACC	p.Pro258_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	1		ENSP00000254846.5	O15054-1
KDM6B	ENST00000570632.1 link	c.711+138_711+158delACCACCACCACCACCACCACC		intron_variant	Intron 7 of 8	5		ENSP00000458445.1	I3L0Z0

Frequencies

GnomAD3 genomes

AF:

0.0000930

AC:

AN:

118290

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000691

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000857

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000238

Gnomad SAS

AF:

0.000277

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

124

AN:

1097542

Hom.:

AF XY:

0.000101

AC XY:

AN XY:

554650

show subpopulations

African (AFR)

AF:

0.0000782

AC:

AN:

25588

American (AMR)

AF:

0.00

AC:

AN:

38604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22354

East Asian (EAS)

AF:

0.00

AC:

AN:

35632

South Asian (SAS)

AF:

0.0000397

AC:

AN:

75536

European-Finnish (FIN)

AF:

0.0000278

AC:

AN:

35930

Middle Eastern (MID)

AF:

0.000280

AC:

AN:

3566

European-Non Finnish (NFE)

AF:

0.000140

AC:

114

AN:

812372

Other (OTH)

AF:

0.0000626

AC:

AN:

47960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.702

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:

0.0000929

AC:

AN:

118352

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

55510

show subpopulations

African (AFR)

AF:

0.0000689

AC:

AN:

29016

American (AMR)

AF:

0.0000856

AC:

AN:

11684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3118

East Asian (EAS)

AF:

0.000239

AC:

AN:

4180

South Asian (SAS)

AF:

0.000278

AC:

AN:

3594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

58162

Other (OTH)

AF:

0.00

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Alfa

AF:

0.00

Hom.:

2265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.7

Mutation Taster

=179/21

polymorphism

(source)

Splicing

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

Publications

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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