rs3735156

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_170606.3(KMT2C):c.1577G>C(p.Arg526Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 1,612,278 control chromosomes in the GnomAD database, including 9,481 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R526H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 4565 hom., cov: 32)

Exomes 𝑓: 0.037 ( 4916 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 1.51

Publications

26 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029095411).

BP6

Variant 7-152251983-C-G is Benign according to our data. Variant chr7-152251983-C-G is described in ClinVar as Benign. ClinVar VariationId is 134740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

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.1577G>C	p.Arg526Pro	missense	Exon 11 of 59	NP_733751.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.1577G>C	p.Arg526Pro	missense	Exon 11 of 59	ENSP00000262189.6
KMT2C	ENST00000682283.1		c.1577G>C	p.Arg526Pro	missense	Exon 11 of 60	ENSP00000507485.1
KMT2C	ENST00000679882.1		c.1577G>C	p.Arg526Pro	missense	Exon 11 of 56	ENSP00000506154.1

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22736

AN:

152042

Hom.:

4537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.457

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0894

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.0855

Gnomad SAS

AF:

0.0917

Gnomad FIN

AF:

0.0247

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0711

AC:

17787

AN:

250254

AF XY:

0.0624

show subpopulations

Gnomad AFR exome

AF:

0.469

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0836

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0451

GnomAD4 exome

AF:

0.0367

AC:

53543

AN:

1460118

Hom.:

4916

Cov.:

AF XY:

0.0364

AC XY:

26456

AN XY:

726214

show subpopulations

African (AFR)

AF:

0.473

AC:

15793

AN:

33396

American (AMR)

AF:

0.103

AC:

4620

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

377

AN:

26112

East Asian (EAS)

AF:

0.0902

AC:

3579

AN:

39660

South Asian (SAS)

AF:

0.0823

AC:

7056

AN:

85774

European-Finnish (FIN)

AF:

0.0213

AC:

1135

AN:

53330

Middle Eastern (MID)

AF:

0.0438

AC:

252

AN:

5756

European-Non Finnish (NFE)

AF:

0.0157

AC:

17419

AN:

1111126

Other (OTH)

AF:

0.0549

AC:

3312

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1909

3818

5727

7636

9545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1036

2072

3108

4144

5180

<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

AF:

0.150

AC:

22815

AN:

152160

Hom.:

4565

Cov.:

AF XY:

0.148

AC XY:

11032

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.457

AC:

18953

AN:

41458

American (AMR)

AF:

0.0896

AC:

1370

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3466

East Asian (EAS)

AF:

0.0853

AC:

442

AN:

5182

South Asian (SAS)

AF:

0.0914

AC:

441

AN:

4826

European-Finnish (FIN)

AF:

0.0247

AC:

262

AN:

10602

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0157

AC:

1067

AN:

68014

Other (OTH)

AF:

0.103

AC:

217

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

699

1398

2098

2797

3496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.0271

Hom.:

209

Bravo

AF:

0.168

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.453

AC:

1996

ESP6500EA

AF:

0.0162

AC:

139

ExAC

AF:

0.0762

AC:

9251

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.033

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.13

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Benign

2.2

REVEL

Uncertain

0.40

Sift

Benign

1.0

Polyphen

0.0

Vest4

0.032

MPC

0.046

ClinPred

0.0046

GERP RS

5.8

Varity_R

0.13

gMVP

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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