7-152162598-G-A

Variant names:

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.10979C>T(p.Ser3660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,614,162 control chromosomes in the GnomAD database, including 2,196 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. S3660W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.036 ( 158 hom., cov: 32)

Exomes 𝑓: 0.045 ( 2038 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.97

Publications

30 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=0.0015626252).

BP6

Variant 7-152162598-G-A is Benign according to our data. Variant chr7-152162598-G-A is described in ClinVar as Benign. ClinVar VariationId is 134792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.10979C>T	p.Ser3660Leu	missense	Exon 43 of 59	NP_733751.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.10979C>T	p.Ser3660Leu	missense	Exon 43 of 59	ENSP00000262189.6
KMT2C	ENST00000360104.8	TSL:1	c.6599C>T	p.Ser2200Leu	missense	Exon 15 of 31	ENSP00000353218.4
KMT2C	ENST00000473186.5	TSL:1	n.8690C>T		non_coding_transcript_exon	Exon 29 of 46

Frequencies

GnomAD3 genomes

AF:

0.0359

AC:

5462

AN:

152174

Hom.:

159

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00866

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.0770

Gnomad FIN

AF:

0.0308

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0429

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0477

AC:

11984

AN:

251438

AF XY:

0.0497

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.0333

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0347

GnomAD4 exome

AF:

0.0453

AC:

66282

AN:

1461870

Hom.:

2038

Cov.:

AF XY:

0.0463

AC XY:

33697

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00556

AC:

186

AN:

33480

American (AMR)

AF:

0.0233

AC:

1044

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

586

AN:

26136

East Asian (EAS)

AF:

0.172

AC:

6832

AN:

39700

South Asian (SAS)

AF:

0.0697

AC:

6009

AN:

86242

European-Finnish (FIN)

AF:

0.0305

AC:

1627

AN:

53420

Middle Eastern (MID)

AF:

0.0284

AC:

164

AN:

5768

European-Non Finnish (NFE)

AF:

0.0424

AC:

47136

AN:

1112004

Other (OTH)

AF:

0.0447

AC:

2698

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4078

8156

12234

16312

20390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1858

3716

5574

7432

9290

<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:

0.0359

AC:

5462

AN:

152292

Hom.:

158

Cov.:

AF XY:

0.0370

AC XY:

2757

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00864

AC:

359

AN:

41570

American (AMR)

AF:

0.0256

AC:

391

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3472

East Asian (EAS)

AF:

0.167

AC:

863

AN:

5176

South Asian (SAS)

AF:

0.0766

AC:

369

AN:

4816

European-Finnish (FIN)

AF:

0.0308

AC:

327

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0430

AC:

2922

AN:

68020

Other (OTH)

AF:

0.0364

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

258

516

774

1032

1290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0433

Hom.:

679

Bravo

AF:

0.0352

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0467

AC:

180

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0383

AC:

329

ExAC

AF:

0.0477

AC:

5788

Asia WGS

AF:

0.0960

AC:

333

AN:

3478

EpiCase

AF:

0.0413

EpiControl

AF:

0.0374

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

3.8

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.12

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

2.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Benign

0.36

Sift4G

Benign

0.78

Polyphen

0.0020

Vest4

0.067

MPC

0.070

ClinPred

0.014

GERP RS

1.7

Varity_R

0.060

gMVP

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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