19-35718023-C-CGGCGGCGGCG

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.15_24dup(p.Ser9GlyfsTer110) variant causes a frameshift 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.131

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 19-35718023-C-CGGCGGCGGCG is Pathogenic according to our data. Variant chr19-35718023-C-CGGCGGCGGCG is described in ClinVar as [Pathogenic]. Clinvar id is 817423.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.15_24dup	p.Ser9GlyfsTer110	frameshift_variant	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.15_24dup	p.Ser9GlyfsTer110	frameshift_variant	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.15_24dup	p.Ser9GlyfsTer110	frameshift_variant	1/37			A2
KMT2B	ENST00000687718.1	c.15_24dup	p.Ser9GlyfsTer110	frameshift_variant, NMD_transcript_variant	1/3
KMT2B	ENST00000692961.1	c.15_24dup	p.Ser9GlyfsTer110	frameshift_variant, NMD_transcript_variant	1/36

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 05, 2021	ClinVar contains an entry for this variant (Variation ID: 817423). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with KMT2B-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Ser9Glyfs*110) in the KMT2B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KMT2B are known to be pathogenic (PMID: 27839873, 27992417). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2020	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) Has not been previously published as pathogenic or benign to our knowledge -

Dystonia 28, childhood-onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. This variant has been reported as pathogenic (ClinVar ID: VCV000817423). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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: rs1599665134; hg19: chr19-36208925;