19-35720606-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_014727.3(KMT2B):c.1259C>G(p.Pro420Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,493,440 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

KMT2B
NM_014727.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.23

Publications

1 publications found

Variant links:

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)

KMT2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07211739).

BP6

Variant 19-35720606-C-G is Benign according to our data. Variant chr19-35720606-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521800.

BS2

High AC in GnomAd4 at 8 Unknown,AD gene.

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>G	p.Pro420Arg	missense	Exon 3 of 37	NP_055542.1	Q9UMN6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.1259C>G	p.Pro420Arg	missense	Exon 3 of 37	ENSP00000398837.2	Q9UMN6
KMT2B	ENST00000673918.2		c.1193C>G	p.Pro398Arg	missense	Exon 3 of 37	ENSP00000501283.1	A0A669KBI7
KMT2B	ENST00000689139.1		c.755C>G	p.Pro252Arg	missense	Exon 1 of 4	ENSP00000509761.1	A0A8I5KVT4

Frequencies

GnomAD3 genomes

AF:

0.0000546

AC:

AN:

146404

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000204

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

GnomAD2 exomes

AF:

0.0000184

AC:

AN:

108898

AF XY:

0.0000358

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.0000516

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000594

AC:

AN:

1347036

Hom.:

Cov.:

AF XY:

0.00000607

AC XY:

AN XY:

659460

show subpopulations

African (AFR)

AF:

0.000201

AC:

AN:

29906

American (AMR)

AF:

0.0000328

AC:

AN:

30472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21966

East Asian (EAS)

AF:

0.00

AC:

AN:

35380

South Asian (SAS)

AF:

0.00

AC:

AN:

70470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3878

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1052262

Other (OTH)

AF:

0.0000180

AC:

AN:

55668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000546

AC:

AN:

146404

Hom.:

Cov.:

AF XY:

0.0000422

AC XY:

AN XY:

71116

show subpopulations

African (AFR)

AF:

0.000204

AC:

AN:

39188

American (AMR)

AF:

0.00

AC:

AN:

14582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

4878

South Asian (SAS)

AF:

0.00

AC:

AN:

4466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66424

Other (OTH)

AF:

0.00

AC:

AN:

1978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000843

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.030

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.41

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.55

PhyloP100

1.2

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

0.0

Vest4

0.20

MutPred

0.33

Loss of glycosylation at P420 (P = 0.0047)

MVP

0.17

ClinPred

0.071

GERP RS

1.7

Varity_R

0.049

gMVP

0.22

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over