Genetic Variant NM_170606.3:c.2534G>A (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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.2534G>A	p.Gly845Glu	missense splice_region	Exon 15 of 59	NP_733751.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.2534G>A	p.Gly845Glu	missense splice_region	Exon 15 of 59	ENSP00000262189.6
KMT2C	ENST00000473186.5	TSL:1	n.245G>A		non_coding_transcript_exon	Exon 1 of 46
KMT2C	ENST00000682283.1		c.2534G>A	p.Gly845Glu	missense splice_region	Exon 15 of 60	ENSP00000507485.1

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 v4.9

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0064

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.1

PhyloP100

7.3

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Polyphen

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over