12-49051419-C-CG

Position:

• chr12-49051419-C-CG

Variant summary

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

The NM_003482.4(KMT2D):​c.2263_2264insC​(p.Arg755ProfsTer3) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.59

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49051419-C-CG is Pathogenic according to our data. Variant chr12-49051419-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.2263_2264insC	p.Arg755ProfsTer3	frameshift_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.2263_2264insC	p.Arg755ProfsTer3	frameshift_variant	11/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.2263_2264insC	p.Arg755ProfsTer3	frameshift_variant	11/56			P4
KMT2D	ENST00000685166.1	c.2263_2264insC	p.Arg755ProfsTer3	frameshift_variant	10/54			A2
KMT2D	ENST00000692637.1	c.2263_2264insC	p.Arg755ProfsTer3	frameshift_variant	10/54			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 14, 2021	The KMT2D c.2263dup variant is located in exon 11/55 and is predicted to cause a shift in the reading frame at codon 755, resulting in premature termination and likely non-sense mediated decay of the resulting protein product (PVS1). This variant has been identified as a de novo variant in this patient with no family history of this condition and de novo variants are a known mechanism of disease (PS2). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs1555196984). The variant has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 547407). This variant has not been reported in the HGMD disease database. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, no assertion criteria provided	research	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	Sep 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

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: rs1555196984; hg19: chr12-49445202;