19-35718023-C-CGGCGGCGGCG

Position:

• chr19-35718023-C-CGGCGGCGGCG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_014727.3(KMT2B):​c.15_24dupGGGCGGCGGC​(p.Ser9fs) 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:4
• 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]

KMT2B (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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 13 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	Protein	UniProt
KMT2B	NM_014727.3	c.15_24dupGGGCGGCGGC	p.Ser9fs	frameshift_variant	1/37	ENST00000420124.4	NP_055542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2B	ENST00000420124.4	c.15_24dupGGGCGGCGGC	p.Ser9fs	frameshift_variant	1/37	1	NM_014727.3	ENSP00000398837.2
KMT2B	ENST00000673918.2	c.15_24dupGGGCGGCGGC	p.Ser9fs	frameshift_variant	1/37			ENSP00000501283.1
KMT2B	ENST00000687718.1	n.15_24dupGGGCGGCGGC		non_coding_transcript_exon_variant	1/3			ENSP00000510535.1
KMT2B	ENST00000692961.1	n.15_24dupGGGCGGCGGC		non_coding_transcript_exon_variant	1/36			ENSP00000509289.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	GeneDx	Aug 20, 2024	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 at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). -

Intellectual developmental disorder, autosomal dominant 68 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 19, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with childhood-onset dystonia 28 (MIM#617284) and autosomal dominant intellectual developmental disorder 68 (MIM#619934). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Rarely, inheritance from an asymptomatic parent has been reported for missense variants (PMID: 33150406). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic and in individuals with KMT2B-related disorders (ClinVar, PMID: 33150406). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by multiple clinical testing laboratories, including in an individual with dystonia and syndromic global developmental delay (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis, confirmed by Sanger sequencing). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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;