X-53196882-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004187.5(KDM5C):c.2785C>G(p.Arg929Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,200,844 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Publications

4 publications found

Variant links:

Genes affected

KDM5C (HGNC:11114): (lysine demethylase 5C) This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

KDM5C Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Claes-Jensen type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

KDM5C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19370577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5 link	c.2785C>G	p.Arg929Gly	missense_variant	Exon 19 of 26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8 link	c.2785C>G	p.Arg929Gly	missense_variant	Exon 19 of 26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes

AF:

0.00000883

AC:

AN:

113187

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000356

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000639

AC:

AN:

156382

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1087605

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

355201

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26169

American (AMR)

AF:

0.00

AC:

AN:

33818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19177

East Asian (EAS)

AF:

0.00

AC:

AN:

29575

South Asian (SAS)

AF:

0.0000189

AC:

AN:

52785

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39603

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4037

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836799

Other (OTH)

AF:

0.00

AC:

AN:

45642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113239

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35389

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31269

American (AMR)

AF:

0.00

AC:

AN:

10849

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.000357

AC:

AN:

2800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53327

Other (OTH)

AF:

0.00

AC:

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability Claes-Jensen type

Uncertain:1

Sep 09, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2785C>G variant is not present in publicly available population databases like EVS, Indian Exome Database or our in-house exome database. The variant is present in 1000 Genomes, ExAC and gnomAD at a low frequency. This variant has neither been published in literature nor reported to the ClinVar, Human Genome Mutation Database (HGMD) or OMIM databases, in any affected individuals. Predictions from different in-silico pathogenicity prediction programs like SIFT, Polyphen-2, MutationTaster2, CADD etc. are contradictory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

.;T;.;.;.

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.82

T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

.;M;.;M;.

PhyloP100

2.3

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.1

D;D;D;D;D

REVEL

Benign

0.086

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D

Polyphen

0.26

.;B;.;.;.

Vest4

0.33

MutPred

0.61

.;Loss of MoRF binding (P = 0.0144);.;Loss of MoRF binding (P = 0.0144);.;

MVP

0.26

MPC

0.78

ClinPred

0.81

GERP RS

4.4

Varity_R

0.43

gMVP

0.68

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over