19-35720606-C-T

Variant names:

• chr19-35720606-C-T
• rs953781410
• NM_014727.3:c.1259C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014727.3(KMT2B):​c.1259C>T​(p.Pro420Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,347,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P420R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with motor features

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dystonia 28, childhood-onset

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• intellectual developmental disorder, autosomal dominant 68

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09274536).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014727.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2B	NM_014727.3	MANE Select	c.1259C>T	p.Pro420Leu	missense	Exon 3 of 37	NP_055542.1	Q9UMN6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.1259C>T	p.Pro420Leu	missense	Exon 3 of 37	ENSP00000398837.2	Q9UMN6
	KMT2B	ENST00000673918.2		c.1193C>T	p.Pro398Leu	missense	Exon 3 of 37	ENSP00000501283.1	A0A669KBI7
	KMT2B	ENST00000689139.1		c.755C>T	p.Pro252Leu	missense	Exon 1 of 4	ENSP00000509761.1	A0A8I5KVT4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1347036 Hom.: 0 Cov.: 34 AF XY: 0.00000303 AC XY: 2 AN XY: 659460

African (AFR) AF: 0.00 AC: 0 AN: 29906

American (AMR) AF: 0.0000328 AC: 1 AN: 30472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21966

East Asian (EAS) AF: 0.00 AC: 0 AN: 35380

South Asian (SAS) AF: 0.00 AC: 0 AN: 70470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3878

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052262

Other (OTH) AF: 0.00 AC: 0 AN: 55668

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0	B
Vest4		0.24
MutPred		0.35		Loss of glycosylation at P420 (P = 0.0047)
MVP		0.18
ClinPred		0.16	T
GERP RS		1.7
Varity_R		0.063
gMVP		0.20
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs953781410; hg19: chr19-36211508;