NM_001348716.2:c.184C>G

Variant names:

• chr17-7845918-C-G
• rs144535196
• NM_001348716.2:c.184C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001348716.2(KDM6B):​c.184C>G​(p.Pro62Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P62S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KDM6B NM_001348716.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• Publications: 2 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: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13758376).

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.184C>G	p.Pro62Ala	missense	Exon 6 of 24	NP_001335645.1	O15054-2
	KDM6B	NM_001080424.2		c.184C>G	p.Pro62Ala	missense	Exon 5 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.184C>G	p.Pro62Ala	missense	Exon 6 of 24	ENSP00000412513.2	O15054-2
	KDM6B	ENST00000254846.9	TSL:1	c.184C>G	p.Pro62Ala	missense	Exon 5 of 22	ENSP00000254846.5	O15054-1
	KDM6B	ENST00000911119.1		c.184C>G	p.Pro62Ala	missense	Exon 5 of 22	ENSP00000581178.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251448 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.10
Sift	Benign	0.15	T
Sift4G	Uncertain	0.027	D
Polyphen		0.85	P
Vest4		0.51
MutPred		0.32		Loss of glycosylation at P62 (P = 0.021)
MVP		0.20
MPC		0.11
ClinPred		0.22	T
GERP RS		4.0
Varity_R		0.055
gMVP		0.50
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs144535196; hg19: chr17-7749236;