X-53201926-G-C

Variant names:

• chrX-53201926-G-C
• rs35353912
• NM_004187.5:c.1794C>G

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.1794C>G​(p.Pro598Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,210,528 control chromosomes in the GnomAD database, including 6 homozygotes. There are 211 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P598P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., 102 hem., cov: 23)
  • Exomes 𝑓: 0.00038 (4 hom. 109 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.806
• Publications: 3 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, Labcorp Genetics (formerly Invitae), G2P, 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=-0.49).
• BP6: Variant X-53201926-G-C is Benign according to our data. Variant chrX-53201926-G-C is described in ClinVar as Benign. ClinVar VariationId is 695652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.806 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00371 (417/112380) while in subpopulation AFR AF = 0.013 (401/30901). AF 95% confidence interval is 0.0119. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	NM_004187.5	MANE Select	c.1794C>G	p.Pro598Pro	synonymous	Exon 13 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.1791C>G	p.Pro597Pro	synonymous	Exon 13 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.1794C>G	p.Pro598Pro	synonymous	Exon 13 of 26	NP_001340907.1	P41229-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.1794C>G	p.Pro598Pro	synonymous	Exon 13 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.1791C>G	p.Pro597Pro	synonymous	Exon 13 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.1896C>G	p.Pro632Pro	synonymous	Exon 14 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 415 AN: 112328 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000848

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.00111 AC: 204 AN: 183514 AF XY: 0.000721

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.000255

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: 0.000381 AC: 418 AN: 1098148 Hom.: 4 Cov.: 30 AF XY: 0.000300 AC XY: 109 AN XY: 363502

African (AFR) AF: 0.0137 AC: 362 AN: 26402

American (AMR) AF: 0.000227 AC: 8 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.000483 AC: 2 AN: 4137

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842038

Other (OTH) AF: 0.000889 AC: 41 AN: 46094

GnomAD4 genome AF: 0.00371 AC: 417 AN: 112380 Hom.: 2 Cov.: 23 AF XY: 0.00295 AC XY: 102 AN XY: 34546

African (AFR) AF: 0.0130 AC: 401 AN: 30901

American (AMR) AF: 0.000847 AC: 9 AN: 10628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6173

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53269

Other (OTH) AF: 0.00262 AC: 4 AN: 1524

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.00411

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	KDM5C-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.9
DANN	Benign	0.71
PhyloP100		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs35353912; hg19: chrX-53231108; COSMIC: COSV104428176;