dbSNP rs4024419: KMT2C:p.Gly845Ala (chr7-152238825-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_170606.3(KMT2C):c.2534G>C(p.Gly845Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000874 in 114,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000087 ( 0 hom., cov: 32)

Consequence

KMT2C
NM_170606.3 missense, splice_region

Scores

Splicing: ADA: 0.9617

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.31

Publications

18 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Kleefstra syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics, Broad Center for Mendelian Genomics
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

KMT2C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2C	NM_170606.3 link	c.2534G>C	p.Gly845Ala	missense_variant, splice_region_variant	Exon 15 of 59	ENST00000262189.11	NP_733751.2	Q8NEZ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11 link	c.2534G>C	p.Gly845Ala	missense_variant, splice_region_variant	Exon 15 of 59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00000874

AC:

AN:

114400

Hom.:

Cov.:

show subpopulations

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:

0.0000196

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000874

AC:

AN:

114400

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

55392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31542

American (AMR)

AF:

0.00

AC:

AN:

11020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2668

East Asian (EAS)

AF:

0.00

AC:

AN:

4148

South Asian (SAS)

AF:

0.00

AC:

AN:

3726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.0000196

AC:

AN:

51132

Other (OTH)

AF:

0.00

AC:

AN:

1588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

7.3

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.010

D;D

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.14

Loss of methylation at K843 (P = 0.1141);Loss of methylation at K843 (P = 0.1141);

MVP

0.86

MPC

2.5

ClinPred

0.95

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.28

gMVP

0.67

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.82

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