Genetic Variant NM_015061.6:c.2299C>G (chr9-7046901-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015061.6(KDM4C):c.2299C>G(p.Gln767Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,594,768 control chromosomes in the GnomAD database, including 32,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2538 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29712 hom. )

Consequence

KDM4C
NM_015061.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.20

Publications

25 publications found

Variant links:

Genes affected

KDM4C (HGNC:17071): (lysine demethylase 4C) This gene is a member of the Jumonji domain 2 (JMJD2) family. The encoded protein is a trimethylation-specific demethylase, and converts specific trimethylated histone residues to the dimethylated form. This enzymatic action regulates gene expression and chromosome segregation. Chromosomal aberrations and changes in expression of this gene may be found in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

KDM4C links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002591759).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4C	NM_015061.6 link	c.2299C>G	p.Gln767Glu	missense_variant	Exon 16 of 22	ENST00000381309.8	NP_055876.2	Q9H3R0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM4C	ENST00000381309.8 link	c.2299C>G	p.Gln767Glu	missense_variant	Exon 16 of 22	1	NM_015061.6	ENSP00000370710.3		Q9H3R0-1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23902

AN:

151890

Hom.:

2535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0559

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.398

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.219

AC:

54756

AN:

250218

AF XY:

0.224

show subpopulations

Gnomad AFR exome

AF:

0.0473

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.152

Gnomad EAS exome

AF:

0.277

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.191

AC:

274950

AN:

1442760

Hom.:

29712

Cov.:

AF XY:

0.196

AC XY:

140818

AN XY:

718734

show subpopulations

African (AFR)

AF:

0.0467

AC:

1552

AN:

33222

American (AMR)

AF:

0.333

AC:

14786

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3926

AN:

25948

East Asian (EAS)

AF:

0.239

AC:

9460

AN:

39540

South Asian (SAS)

AF:

0.378

AC:

32307

AN:

85374

European-Finnish (FIN)

AF:

0.127

AC:

6766

AN:

53368

Middle Eastern (MID)

AF:

0.148

AC:

850

AN:

5736

European-Non Finnish (NFE)

AF:

0.177

AC:

193835

AN:

1095432

Other (OTH)

AF:

0.192

AC:

11468

AN:

59676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

9415

18830

28244

37659

47074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7052

14104

21156

28208

35260

<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:

0.157

AC:

23911

AN:

152008

Hom.:

2538

Cov.:

AF XY:

0.162

AC XY:

12050

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.0558

AC:

2318

AN:

41520

American (AMR)

AF:

0.271

AC:

4130

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

530

AN:

3466

East Asian (EAS)

AF:

0.267

AC:

1378

AN:

5156

South Asian (SAS)

AF:

0.399

AC:

1918

AN:

4812

European-Finnish (FIN)

AF:

0.114

AC:

1212

AN:

10598

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.174

AC:

11842

AN:

67922

Other (OTH)

AF:

0.163

AC:

344

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

969

1938

2906

3875

4844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.174

Hom.:

1869

Bravo

AF:

0.159

TwinsUK

AF:

0.191

AC:

710

ALSPAC

AF:

0.180

AC:

693

ESP6500AA

AF:

0.0529

AC:

233

ESP6500EA

AF:

0.177

AC:

1519

ExAC

AF:

0.215

AC:

26067

Asia WGS

AF:

0.311

AC:

1077

AN:

3478

EpiCase

AF:

0.173

EpiControl

AF:

0.172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.012

.;.;T;.;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.55

T;T;T;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

.;L;L;L;.;.

PhyloP100

2.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.93

.;N;N;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.31

.;T;T;T;T;T

Sift4G

Benign

0.42

.;T;T;T;T;T

Polyphen

0.0010, 0.0

.;B;B;.;.;.

Vest4

0.035, 0.056, 0.092, 0.087

MPC

0.042

ClinPred

0.0057

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.081

gMVP

0.46

Mutation Taster

=99/1

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

Computational scores

Splicing

Publications

Other links and lift over