17-7845897-C-T

Variant names:

• chr17-7845897-C-T
• rs2078523375
• NM_001348716.2:c.163C>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.163C>T​(p.Pro55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P55P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM6B NM_001348716.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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]

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=0.15242925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6B	NM_001348716.2	c.163C>T	p.Pro55Ser	missense_variant	Exon 6 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.163C>T	p.Pro55Ser	missense_variant	Exon 5 of 22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.163C>T	p.Pro55Ser	missense_variant	Exon 6 of 24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.163C>T	p.Pro55Ser	missense_variant	Exon 5 of 22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.163C>T	p.Pro55Ser	missense_variant	Exon 4 of 9	5		ENSP00000458445.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163C>T (p.P55S) alteration is located in exon 5 (coding exon 2) of the KDM6B gene. This alteration results from a C to T substitution at nucleotide position 163, causing the proline (P) at amino acid position 55 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.32	N;N;.
REVEL	Benign	0.043
Sift	Uncertain	0.0080	D;D;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.22	B;.;.
Vest4		0.47
MutPred		0.23		Loss of catalytic residue at P54 (P = 0.0117);Loss of catalytic residue at P54 (P = 0.0117);Loss of catalytic residue at P54 (P = 0.0117);
MVP		0.10
MPC		0.12
ClinPred		0.48	T
GERP RS		4.0
Varity_R		0.084
gMVP		0.42

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: rs2078523375; hg19: chr17-7749215;