chr7-152252650-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_170606.3(KMT2C):c.1365A>G(p.Ile455Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,613,196 control chromosomes in the GnomAD database, including 1,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. I455V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 77 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1167 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.0770

Publications

14 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=0.0062871873).

BP6

Variant 7-152252650-T-C is Benign according to our data. Variant chr7-152252650-T-C is described in ClinVar as [Benign]. Clinvar id is 134736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.025 (3815/152324) while in subpopulation NFE AF = 0.0401 (2726/68018). AF 95% confidence interval is 0.0388. There are 77 homozygotes in GnomAd4. There are 1743 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3815 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2C	NM_170606.3 link	c.1365A>G	p.Ile455Met	missense_variant	Exon 10 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.1365A>G	p.Ile455Met	missense_variant	Exon 10 of 59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3817

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00704

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0238

AC:

5971

AN:

250670

AF XY:

0.0241

show subpopulations

Gnomad AFR exome

AF:

0.00640

Gnomad AMR exome

AF:

0.0170

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0368

AC:

53792

AN:

1460872

Hom.:

1167

Cov.:

AF XY:

0.0358

AC XY:

26049

AN XY:

726778

show subpopulations

African (AFR)

AF:

0.00598

AC:

200

AN:

33464

American (AMR)

AF:

0.0172

AC:

767

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

458

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.00589

AC:

508

AN:

86228

European-Finnish (FIN)

AF:

0.0245

AC:

1310

AN:

53366

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0438

AC:

48689

AN:

1111224

Other (OTH)

AF:

0.0298

AC:

1800

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2351

4702

7052

9403

11754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0250

AC:

3815

AN:

152324

Hom.:

Cov.:

AF XY:

0.0234

AC XY:

1743

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00702

AC:

292

AN:

41590

American (AMR)

AF:

0.0218

AC:

334

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00601

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0268

AC:

284

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0401

AC:

2726

AN:

68018

Other (OTH)

AF:

0.0237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

188

376

565

753

941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0344

Hom.:

349

Bravo

AF:

0.0241

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0434

AC:

373

ExAC

AF:

0.0230

AC:

2790

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0361

EpiControl

AF:

0.0382

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1Other:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.095

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.85

.;T

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.35

N;N

PhyloP100

-0.077

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.20

Sift

Benign

0.15

T;T

Polyphen

0.0040

B;B

Vest4

0.17

MPC

0.039

ClinPred

0.0034

GERP RS

-5.2

PromoterAI

0.0070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.060

gMVP

0.17

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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chr7-152252650-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over