6-18217725-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001364614.2(KDM1B):c.2233-8G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,609,876 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00067 (11 hom.)
• Consequence: KDM1B NM_001364614.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007941
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0210

Genes affected

KDM1B (HGNC:21577): (lysine demethylase 1B) Flavin-dependent histone demethylases, such as KDM1B, regulate histone lysine methylation, an epigenetic mark that regulates gene expression and chromatin function (Karytinos et al., 2009 [PubMed 19407342]).[supplied by OMIM, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-18217725-G-C is Benign according to our data. Variant chr6-18217725-G-C is described in ClinVar as [Benign]. Clinvar id is 775230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00605 (919/151804) while in subpopulation AFR AF= 0.0191 (790/41366). AF 95% confidence interval is 0.018. There are 11 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM1B	NM_001364614.2	c.2233-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000650836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM1B	ENST00000650836.2	c.2233-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001364614.2	P4

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 919 AN: 151686 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00683

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00161 AC: 399 AN: 248028 Hom.: 5 AF XY: 0.00121 AC XY: 163 AN XY: 134372

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.000669 AC: 976 AN: 1458072 Hom.: 11 Cov.: 30 AF XY: 0.000568 AC XY: 412 AN XY: 725662

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00605 AC: 919 AN: 151804 Hom.: 11 Cov.: 31 AF XY: 0.00615 AC XY: 456 AN XY: 74168

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.00682

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00784

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.63
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.030		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: rs74542809; hg19: chr6-18217956;