X-53217236-C-T

Variant names:

• chrX-53217236-C-T
• rs61751437
• NM_004187.5:c.564G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004187.5(KDM5C):​c.564G>A​(p.Lys188Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,209,118 control chromosomes in the GnomAD database, including 117 homozygotes. There are 5,918 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., 358 hem., cov: 23)
  • Exomes 𝑓: 0.015 (110 hom. 5560 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.798
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-53217236-C-T is Benign according to our data. Variant chrX-53217236-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.798 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0108 (1209/111639) while in subpopulation SAS AF = 0.0181 (48/2647). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004187.5. 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
	KDM5C	NM_004187.5	MANE Select	c.564G>A	p.Lys188Lys	synonymous	Exon 5 of 26	NP_004178.2
	KDM5C	NM_001282622.3		c.561G>A	p.Lys187Lys	synonymous	Exon 5 of 26	NP_001269551.1
	KDM5C	NM_001353978.3		c.564G>A	p.Lys188Lys	synonymous	Exon 5 of 26	NP_001340907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.564G>A	p.Lys188Lys	synonymous	Exon 5 of 26	ENSP00000364550.4
	KDM5C	ENST00000404049.7	TSL:1	c.561G>A	p.Lys187Lys	synonymous	Exon 5 of 26	ENSP00000385394.3
	KDM5C	ENST00000375379.7	TSL:5	c.564G>A	p.Lys188Lys	synonymous	Exon 5 of 26	ENSP00000364528.3

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1210 AN: 111585 Hom.: 7 Cov.: 23

Gnomad AFR AF: 0.00180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0185

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00736

GnomAD2 exomes AF: 0.0131 AC: 2373 AN: 181039 AF XY: 0.0133

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00381

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0155 AC: 16987 AN: 1097479 Hom.: 110 Cov.: 31 AF XY: 0.0153 AC XY: 5560 AN XY: 362849

African (AFR) AF: 0.00125 AC: 33 AN: 26395

American (AMR) AF: 0.00390 AC: 137 AN: 35159

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 251 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0192 AC: 1035 AN: 53984

European-Finnish (FIN) AF: 0.0260 AC: 1052 AN: 40481

Middle Eastern (MID) AF: 0.00655 AC: 27 AN: 4122

European-Non Finnish (NFE) AF: 0.0164 AC: 13839 AN: 841707

Other (OTH) AF: 0.0133 AC: 613 AN: 46055

GnomAD4 genome AF: 0.0108 AC: 1209 AN: 111639 Hom.: 7 Cov.: 23 AF XY: 0.0106 AC XY: 358 AN XY: 33841

African (AFR) AF: 0.00179 AC: 55 AN: 30698

American (AMR) AF: 0.00849 AC: 90 AN: 10603

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 37 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.0181 AC: 48 AN: 2647

European-Finnish (FIN) AF: 0.0197 AC: 119 AN: 6031

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0160 AC: 847 AN: 53053

Other (OTH) AF: 0.00793 AC: 12 AN: 1513

Alfa AF: 0.0140 Hom.: 110

Bravo AF: 0.00838

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 03, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Dec 04, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15586325, 24583395)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Spastic paraplegia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

May 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Syndromic X-linked intellectual disability Claes-Jensen type Benign:1

Aug 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.1
DANN	Benign	0.84
PhyloP100		0.80
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61751437; hg19: chrX-53246418; COSMIC: COSV62891500; COSMIC: COSV62891500;