rs2078514615

Variant names:

• chr17-7845574-C-T
• rs2078514615
• NM_001348716.2:c.20C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001348716.2(KDM6B):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KDM6B NM_001348716.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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]

LOC124904106 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19403309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6B	NM_001348716.2	c.20C>T	p.Pro7Leu	missense_variant	Exon 5 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.20C>T	p.Pro7Leu	missense_variant	Exon 4 of 22		NP_001073893.1
LOC124904106	XM_047437265.1	c.-46G>A		upstream_gene_variant			XP_047293221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.20C>T	p.Pro7Leu	missense_variant	Exon 5 of 24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.20C>T	p.Pro7Leu	missense_variant	Exon 4 of 22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.20C>T	p.Pro7Leu	missense_variant	Exon 3 of 9	5		ENSP00000458445.1
KDM6B	ENST00000571047.5	n.*227C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20C>T (p.P7L) alteration is located in exon 4 (coding exon 1) of the KDM6B gene. This alteration results from a C to T substitution at nucleotide position 20, causing the proline (P) at amino acid position 7 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	.;T;T
Eigen	Benign	0.094
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.40	N;N;.
REVEL	Benign	0.14
Sift	Benign	0.34	T;T;.
Sift4G	Benign	0.091	T;T;D
Polyphen		0.94	P;.;.
Vest4		0.60
MutPred		0.48		Gain of MoRF binding (P = 0.0353);Gain of MoRF binding (P = 0.0353);Gain of MoRF binding (P = 0.0353);
MVP		0.20
MPC		0.12
ClinPred		0.60	D
GERP RS		4.2
Varity_R		0.075
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs2078514615; hg19: chr17-7748892; COSMIC: COSV99642386; COSMIC: COSV99642386;