17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACC

Variant names:

• chr17-7846859-TACC-T
• rs61462443
• NM_001348716.2:c.789_791delACC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_Moderate

The NM_001348716.2(KDM6B):​c.789_791delACC​(p.Pro264del) variant causes a disruptive inframe deletion change. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P263P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (29 hom., cov: 0)
  • Exomes 𝑓: 0.0060 (78 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 3.67
• Publications: 8 publications found

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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001348716.2
• BP6: Variant 17-7846859-TACC-T is Benign according to our data. Variant chr17-7846859-TACC-T is described in ClinVar as Benign. ClinVar VariationId is 1300010.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6B	NM_001348716.2	MANE Select	c.789_791delACC	p.Pro264del	disruptive_inframe_deletion	Exon 10 of 24	NP_001335645.1	O15054-2
	KDM6B	NM_001080424.2		c.789_791delACC	p.Pro264del	disruptive_inframe_deletion	Exon 9 of 22	NP_001073893.1	O15054-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6B	ENST00000448097.7	TSL:5 MANE Select	c.789_791delACC	p.Pro264del	disruptive_inframe_deletion	Exon 10 of 24	ENSP00000412513.2	O15054-2
	KDM6B	ENST00000254846.9	TSL:1	c.789_791delACC	p.Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000254846.5	O15054-1
	KDM6B	ENST00000911119.1		c.789_791delACC	p.Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000581178.1

Frequencies

GnomAD3 genomes AF: 0.00850 AC: 1005 AN: 118290 Hom.: 29 Cov.: 0

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00309

Gnomad ASJ AF: 0.0269

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00926

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00597 AC: 6547 AN: 1097344 Hom.: 78 AF XY: 0.00580 AC XY: 3215 AN XY: 554574

African (AFR) AF: 0.00664 AC: 170 AN: 25584

American (AMR) AF: 0.00246 AC: 95 AN: 38604

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 702 AN: 22350

East Asian (EAS) AF: 0.0867 AC: 3087 AN: 35624

South Asian (SAS) AF: 0.00535 AC: 404 AN: 75536

European-Finnish (FIN) AF: 0.000668 AC: 24 AN: 35928

Middle Eastern (MID) AF: 0.00393 AC: 14 AN: 3566

European-Non Finnish (NFE) AF: 0.00176 AC: 1433 AN: 812198

Other (OTH) AF: 0.0129 AC: 618 AN: 47954

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00844 AC: 999 AN: 118352 Hom.: 29 Cov.: 0 AF XY: 0.00976 AC XY: 542 AN XY: 55510

African (AFR) AF: 0.00803 AC: 233 AN: 29016

American (AMR) AF: 0.00308 AC: 36 AN: 11684

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 84 AN: 3118

East Asian (EAS) AF: 0.117 AC: 490 AN: 4176

South Asian (SAS) AF: 0.0103 AC: 37 AN: 3594

European-Finnish (FIN) AF: 0.00116 AC: 7 AN: 6038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.00168 AC: 98 AN: 58166

Other (OTH) AF: 0.00916 AC: 14 AN: 1528

Alfa AF: 0.00831 Hom.: 2265

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	KDM6B-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61462443;

hg19: chr17-7750177;

COSMIC: COSV54679247;

COSMIC: COSV54679247;