Variant 12-49051742-TG-TGG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003482.4(KMT2D):c.1940_1941insC(p.Pro648ThrfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,119,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000011 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.50

Variant links:

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]

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 12-49051742-T-TG is Pathogenic according to our data. Variant chr12-49051742-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 432829.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.1940_1941insC	p.Pro648ThrfsTer2	frameshift_variant	11/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.1940_1941insC	p.Pro648ThrfsTer2	frameshift_variant	11/55	5	NM_003482.4	ENSP00000301067	A2	O14686-1
KMT2D	ENST00000683543.2 linkuse as main transcript	c.1940_1941insC	p.Pro648ThrfsTer2	frameshift_variant	11/56			ENSP00000506726	P4
KMT2D	ENST00000685166.1 linkuse as main transcript	c.1940_1941insC	p.Pro648ThrfsTer2	frameshift_variant	10/54			ENSP00000509386	A2	O14686-3
KMT2D	ENST00000692637.1 linkuse as main transcript	c.1940_1941insC	p.Pro648ThrfsTer2	frameshift_variant	10/54			ENSP00000509666	A2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

95132

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000195

AC:

AN:

1024754

Hom.:

Cov.:

AF XY:

0.00000194

AC XY:

AN XY:

514562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000258

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000105

AC:

AN:

95206

Hom.:

Cov.:

AF XY:

0.0000219

AC XY:

AN XY:

45592

show subpopulations

Gnomad4 AFR

AF:

0.0000409

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2017

The c.1940dupC variant in the KMT2D gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1940dupC variant causes a frameshift starting with codon Proline 648, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p..Pro648ThrfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1940dupC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1940dupC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over