rs28522267

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP4_StrongBP6_Very_Strong

The NM_170606.3(KMT2C):c.2963G>T(p.Cys988Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 0 hom., cov: 42)

Exomes 𝑓: 0.49 ( 39 hom. )

Failed GnomAD Quality Control

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.90

Publications

39 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: Benign. The variant received -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.008740902).

BP6

Variant 7-152229936-C-A is Benign according to our data. Variant chr7-152229936-C-A is described in ClinVar as Benign. ClinVar VariationId is 403019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.2963G>T	p.Cys988Phe	missense	Exon 18 of 59	NP_733751.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.2963G>T	p.Cys988Phe	missense	Exon 18 of 59	ENSP00000262189.6
KMT2C	ENST00000473186.5	TSL:1	n.674G>T		non_coding_transcript_exon	Exon 4 of 46
KMT2C	ENST00000682283.1		c.2963G>T	p.Cys988Phe	missense	Exon 18 of 60	ENSP00000507485.1

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

46723

AN:

108170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.343

Gnomad SAS

AF:

0.366

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.404

GnomAD2 exomes

AF:

0.198

AC:

27538

AN:

139298

AF XY:

0.177

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.229

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.303

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.488

AC:

634391

AN:

1300290

Hom.:

Cov.:

AF XY:

0.488

AC XY:

315602

AN XY:

647150

show subpopulations

African (AFR)

AF:

0.468

AC:

12567

AN:

26874

American (AMR)

AF:

0.485

AC:

18887

AN:

38962

Ashkenazi Jewish (ASJ)

AF:

0.468

AC:

9973

AN:

21292

East Asian (EAS)

AF:

0.469

AC:

14135

AN:

30134

South Asian (SAS)

AF:

0.492

AC:

38529

AN:

78332

European-Finnish (FIN)

AF:

0.479

AC:

21993

AN:

45960

Middle Eastern (MID)

AF:

0.469

AC:

1594

AN:

3400

European-Non Finnish (NFE)

AF:

0.490

AC:

492288

AN:

1004250

Other (OTH)

AF:

0.478

AC:

24425

AN:

51086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

19194

38387

57581

76774

95968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20182

40364

60546

80728

100910

<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: InbreedingCoeff

AF:

0.432

AC:

46735

AN:

108214

Hom.:

Cov.:

AF XY:

0.431

AC XY:

23365

AN XY:

54184

show subpopulations

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

African (AFR)

AF:

0.405

AC:

10806

AN:

26694

American (AMR)

AF:

0.404

AC:

4250

AN:

10532

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

1094

AN:

2396

East Asian (EAS)

AF:

0.343

AC:

1253

AN:

3650

South Asian (SAS)

AF:

0.368

AC:

1218

AN:

3310

European-Finnish (FIN)

AF:

0.421

AC:

3226

AN:

7670

Middle Eastern (MID)

AF:

0.144

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.464

AC:

23872

AN:

51460

Other (OTH)

AF:

0.403

AC:

647

AN:

1606

⚠️ 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: 0.325

Heterozygous variant carriers

2395

4790

7185

9580

11975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

638

1276

1914

2552

3190

<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:

0.361

Hom.:

ExAC

AF:

0.105

AC:

12517

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0087

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.5

PhyloP100

7.9

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-9.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MPC

2.9

ClinPred

0.055

GERP RS

4.7

Varity_R

0.95

gMVP

0.92

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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