Genetic Variant KMT2C:p.Gly845Glu (chr7-152238825-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_170606.3(KMT2C):c.2534G>A(p.Gly845Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign 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 0.0060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2C
NM_170606.3 missense, splice_region

Scores

Splicing: ADA: 0.9962

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 1 ACMG points.

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>A	p.Gly845Glu	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>A	p.Gly845Glu	missense_variant, splice_region_variant	Exon 15 of 59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00595

AC:

609

AN:

102386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00548

Gnomad AMI

AF:

0.00692

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00588

Gnomad EAS

AF:

0.00181

Gnomad SAS

AF:

0.00775

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00460

Gnomad OTH

AF:

0.00346

GnomAD2 exomes

AF:

0.0199

AC:

3366

AN:

169090

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00633

AC:

6364

AN:

1005800

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

2953

AN XY:

509428

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00398

AC:

AN:

24344

American (AMR)

AF:

0.00672

AC:

206

AN:

30646

Ashkenazi Jewish (ASJ)

AF:

0.00319

AC:

AN:

20074

East Asian (EAS)

AF:

0.00257

AC:

AN:

28838

South Asian (SAS)

AF:

0.00223

AC:

158

AN:

70774

European-Finnish (FIN)

AF:

0.00213

AC:

AN:

44162

Middle Eastern (MID)

AF:

0.00267

AC:

AN:

3000

European-Non Finnish (NFE)

AF:

0.00729

AC:

5401

AN:

741214

Other (OTH)

AF:

0.00613

AC:

262

AN:

42748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.237

Heterozygous variant carriers

1112

2225

3337

4450

5562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

260

520

780

1040

1300

<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: AS_VQSR

AF:

0.00599

AC:

613

AN:

102412

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

360

AN XY:

49700

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00554

AC:

161

AN:

29070

American (AMR)

AF:

0.0109

AC:

107

AN:

9790

Ashkenazi Jewish (ASJ)

AF:

0.00588

AC:

AN:

2380

East Asian (EAS)

AF:

0.00182

AC:

AN:

3848

South Asian (SAS)

AF:

0.00807

AC:

AN:

3468

European-Finnish (FIN)

AF:

0.0117

AC:

AN:

6840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00460

AC:

206

AN:

44764

Other (OTH)

AF:

0.00413

AC:

AN:

1452

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.238

Heterozygous variant carriers

106

211

317

422

528

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:

0.0268

Hom.:

ExAC

AF:

0.0579

AC:

7026

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

.;D

MetaRNN

Benign

0.0064

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

7.3

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.73

MPC

2.7

ClinPred

0.013

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.61

gMVP

0.72

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over