19-35718020-T-TGGCGGCGGCGGCG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014727.3(KMT2B):c.12_24dup(p.Ser9_?8) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2B NM_014727.3 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.788

Genes affected

KMT2B (HGNC:15840): (lysine methyltransferase 2B) This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines, and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene, however, the full length nature of the shorter transcript is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 95 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35718020-T-TGGCGGCGGCGGCG is Pathogenic according to our data. Variant chr19-35718020-T-TGGCGGCGGCGGCG is described in ClinVar as [Pathogenic]. Clinvar id is 450816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.12_24dup	p.Ser9_?8	frameshift_variant, start_lost	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.12_24dup	p.Ser9_?8	frameshift_variant, start_lost	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.12_24dup	p.Ser9_?8	frameshift_variant, start_lost	1/37			A2
KMT2B	ENST00000687718.1	c.12_24dup	p.Ser9_?8	frameshift_variant, start_lost, NMD_transcript_variant	1/3
KMT2B	ENST00000692961.1	c.12_24dup	p.Ser9_?8	frameshift_variant, start_lost, NMD_transcript_variant	1/36

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33150406) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The c.12_24dup13 (p.S9Gfs*111) alteration, located in exon 1 (coding exon 1) of the KMT2B gene, consists of a duplication of GGCGGGCGGCGGC at position 12, causing a translational frameshift with a predicted alternate stop codon after 111 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in an individual with features consistent with KMT2B-related early-onset complex dystonia (Cif, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Dystonia 28, childhood-onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Apr 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555727493; hg19: chr19-36208922;