rs587777073

Positions:

• chr7-152194506-G-A
• chr7-152194506-G-C
• chr7-152194506-G-T

Variant summary

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

The NM_170606.3(KMT2C):​c.4441C>T​(p.Arg1481*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KMT2C NM_170606.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.07

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

KMT2C (HGNC:):

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 7-152194506-G-A is Pathogenic according to our data. Variant chr7-152194506-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88895.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
KMT2C	NM_170606.3	c.4441C>T	p.Arg1481*	stop_gained	29/59	ENST00000262189.11	NP_733751.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11	c.4441C>T	p.Arg1481*	stop_gained	29/59	1	NM_170606.3	ENSP00000262189.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460106 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726508

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kleefstra syndrome 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2012	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Kleefstra syndrome 2, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Moderate => PVS1 downgraded in strength to Moderate. PM6 => Assumed de novo, but without confirmation of paternity and maternity. -

KMT2C-related NDD Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2017

A variant that is likely pathogenic has been identified in the KMT2C gene. The R1481X variant has been reported previously as apparently de novo in an individual with intellectual disability, hypotonia, behavioral problems, and additional features resembling Kleefstra syndrome (Kleefstra et al., 2012). This variant is a nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease. It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, the R1481X variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.92
GERP RS		5.7

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: rs587777073; hg19: chr7-151891591; COSMIC: COSV51431986;