chr7-152180042-G-T

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.7234C>A(p.Pro2412Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,120 control chromosomes in the GnomAD database, including 609 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2412P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 34 hom., cov: 31)

Exomes 𝑓: 0.025 ( 575 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.142

Publications

17 publications found

Variant links:

COSMIC-nc: COSV51503284

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=0.0026199222).

BP6

Variant 7-152180042-G-T is Benign according to our data. Variant chr7-152180042-G-T is described in ClinVar as Benign. ClinVar VariationId is 134768.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 = 0.019 (2900/152258) while in subpopulation NFE AF = 0.0294 (1997/68028). AF 95% confidence interval is 0.0283. There are 34 homozygotes in GnomAd4. There are 1344 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2900 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2C	NM_170606.3 link	c.7234C>A	p.Pro2412Thr	missense_variant	Exon 37 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.7234C>A	p.Pro2412Thr	missense_variant	Exon 37 of 59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2900

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00526

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0294

Gnomad OTH

AF:

0.0267

GnomAD2 exomes

AF:

0.0185

AC:

4646

AN:

251466

AF XY:

0.0188

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00980

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0252

AC:

36781

AN:

1461862

Hom.:

575

Cov.:

AF XY:

0.0246

AC XY:

17896

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00436

AC:

146

AN:

33480

American (AMR)

AF:

0.0105

AC:

471

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

528

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00337

AC:

291

AN:

86258

European-Finnish (FIN)

AF:

0.0172

AC:

919

AN:

53420

Middle Eastern (MID)

AF:

0.0309

AC:

178

AN:

5766

European-Non Finnish (NFE)

AF:

0.0296

AC:

32876

AN:

1111984

Other (OTH)

AF:

0.0227

AC:

1371

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

2049

4098

6146

8195

10244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1186

2372

3558

4744

5930

<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:

0.0190

AC:

2900

AN:

152258

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1344

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00527

AC:

219

AN:

41546

American (AMR)

AF:

0.0218

AC:

333

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0174

AC:

184

AN:

10600

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0294

AC:

1997

AN:

68028

Other (OTH)

AF:

0.0265

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

145

291

436

582

727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0254

Hom.:

232

Bravo

AF:

0.0185

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0292

AC:

251

ExAC

AF:

0.0191

AC:

2320

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0313

EpiControl

AF:

0.0322

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

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

0.060

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.2

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.055

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.72

.;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.95

L;L;.

PhyloP100

-0.14

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.2

N;N;D

REVEL

Benign

0.29

Sift

Benign

0.18

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.042

MPC

0.088

ClinPred

0.0010

GERP RS

-4.4

Varity_R

0.032

gMVP

0.23

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

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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