dbSNP rs769921695: KMT2B:p.Pro446Arg (chr19-35720684-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014727.3(KMT2B):c.1337C>G(p.Pro446Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,331,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P446L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2B
NM_014727.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.130

Publications

3 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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.281574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2B	NM_014727.3 link	c.1337C>G	p.Pro446Arg	missense_variant	Exon 3 of 37	ENST00000420124.4	NP_055542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2B	ENST00000420124.4 link	c.1337C>G	p.Pro446Arg	missense_variant	Exon 3 of 37	1	NM_014727.3	ENSP00000398837.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149956

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

85330

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000225

AC:

AN:

1331192

Hom.:

Cov.:

AF XY:

0.00000307

AC XY:

AN XY:

650920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29054

American (AMR)

AF:

0.00

AC:

AN:

24248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20004

East Asian (EAS)

AF:

0.0000846

AC:

AN:

35476

South Asian (SAS)

AF:

0.00

AC:

AN:

65860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050552

Other (OTH)

AF:

0.00

AC:

AN:

54972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

149956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73074

African (AFR)

AF:

0.00

AC:

AN:

40524

American (AMR)

AF:

0.00

AC:

AN:

15068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5000

South Asian (SAS)

AF:

0.00

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67456

Other (OTH)

AF:

0.00

AC:

AN:

2054

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

0.0011

BayesDel_noAF

Benign

-0.24

CADD

Benign

8.0

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.024

Eigen

Benign

0.046

Eigen_PC

Benign

-0.019

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.69

PhyloP100

0.13

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.10

REVEL

Uncertain

0.32

Sift

Benign

0.044

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.34

MutPred

0.37

Loss of glycosylation at P446 (P = 0.0025);

MVP

0.27

ClinPred

0.73

GERP RS

3.7

Varity_R

0.051

gMVP

0.25

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over