Genetic Variant KDM4C:p.Glu206Asp (chr9-6849689-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_015061.6(KDM4C):c.618G>C(p.Glu206Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,561,342 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 5 hom. )

Consequence

KDM4C
NM_015061.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.74

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010848165).

BP6

Variant 9-6849689-G-C is Benign according to our data. Variant chr9-6849689-G-C is described in ClinVar as [Benign]. Clinvar id is 714420.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4C	NM_015061.6 link	c.618G>C	p.Glu206Asp	missense_variant	Exon 5 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.618G>C	p.Glu206Asp	missense_variant	Exon 5 of 22	1	NM_015061.6	ENSP00000370710.3		Q9H3R0-1

Frequencies

GnomAD3 genomes

AF:

0.00374

AC:

569

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.000963

AC:

230

AN:

238808

Hom.:

AF XY:

0.000659

AC XY:

AN XY:

128968

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.000454

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000361

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.000695

GnomAD4 exome

AF:

0.000373

AC:

526

AN:

1409108

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

209

AN XY:

693666

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.000658

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000765

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.000915

GnomAD4 genome

AF:

0.00379

AC:

577

AN:

152234

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

278

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0134

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.00413

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00124

AC:

151

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;.;T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D;D;D

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.9

.;L;L;L

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.7

.;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.040

.;D;D;D

Sift4G

Benign

0.15

.;T;T;T

Polyphen

0.65, 0.70

.;P;P;.

Vest4

0.68, 0.68, 0.59

MutPred

0.27

.;Loss of ubiquitination at K208 (P = 0.1403);Loss of ubiquitination at K208 (P = 0.1403);Loss of ubiquitination at K208 (P = 0.1403);

MVP

0.61

MPC

0.21

ClinPred

0.017

GERP RS

3.9

Varity_R

0.76

gMVP

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over