17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACCACCACCACC

Variant names:

• chr17-7846859-T-TACCACCACCACC
• rs61462443
• NM_001348716.2:c.780_791dupACCACCACCACC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

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. 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. Variant has been reported in ClinVar as Likely benign (★★).

• 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.250
• 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: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001348716.2
• BP6: Variant 17-7846859-T-TACCACCACCACC is Benign according to our data. Variant chr17-7846859-T-TACCACCACCACC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3037897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	NP_001335645.1	O15054-2
	KDM6B	NM_001080424.2		c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	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.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	ENSP00000412513.2	O15054-2
	KDM6B	ENST00000254846.9	TSL:1	c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22	ENSP00000254846.5	O15054-1
	KDM6B	ENST00000911119.1		c.780_791dupACCACCACCACC	p.Pro261_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22	ENSP00000581178.1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 271 AN: 118286 Hom.: 1 Cov.: 0

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.: 9 Cov.: 43 AF XY: 0.00182 AC XY: 1009 AN XY: 554504

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

African (AFR) AF: 0.00313 AC: 80 AN: 25578

American (AMR) AF: 0.00171 AC: 66 AN: 38600

Ashkenazi Jewish (ASJ) AF: 0.00407 AC: 91 AN: 22352

East Asian (EAS) AF: 0.00907 AC: 323 AN: 35624

South Asian (SAS) AF: 0.00118 AC: 89 AN: 75528

European-Finnish (FIN) AF: 0.00103 AC: 37 AN: 35930

Middle Eastern (MID) AF: 0.00140 AC: 5 AN: 3566

European-Non Finnish (NFE) AF: 0.00157 AC: 1271 AN: 812110

Other (OTH) AF: 0.00209 AC: 100 AN: 47948

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00230 AC: 272 AN: 118348 Hom.: 1 Cov.: 0 AF XY: 0.00211 AC XY: 117 AN XY: 55506

African (AFR) AF: 0.00314 AC: 91 AN: 29014

American (AMR) AF: 0.00214 AC: 25 AN: 11682

Ashkenazi Jewish (ASJ) AF: 0.00481 AC: 15 AN: 3118

East Asian (EAS) AF: 0.00789 AC: 33 AN: 4180

South Asian (SAS) AF: 0.000835 AC: 3 AN: 3594

European-Finnish (FIN) AF: 0.00116 AC: 7 AN: 6036

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

European-Non Finnish (NFE) AF: 0.00167 AC: 97 AN: 58164

Other (OTH) AF: 0.000654 AC: 1 AN: 1528

Alfa AF: 0.00 Hom.: 2265

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	KDM6B-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
Mutation Taster		=89/11	polymorphism

Splicing

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;