rs6022993

Variant names:

• chr20-54162708-C-T
• rs6022993
• NM_000782.5:c.990+9G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_000782.5(CYP24A1):​c.990+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,577,294 control chromosomes in the GnomAD database, including 2,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (1288 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (1162 hom.)
• Consequence: CYP24A1 NM_000782.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0790

Genes affected

CYP24A1 (HGNC:2602): (cytochrome P450 family 24 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein initiates the degradation of 1,25-dihydroxyvitamin D3, the physiologically active form of vitamin D3, by hydroxylation of the side chain. In regulating the level of vitamin D3, this enzyme plays a role in calcium homeostasis and the vitamin D endocrine system. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 20-54162708-C-T is Benign according to our data. Variant chr20-54162708-C-T is described in ClinVar as [Benign]. Clinvar id is 338821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54162708-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.990+9G>A		intron_variant	Intron 7 of 11	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.990+9G>A		intron_variant	Intron 7 of 11	1	NM_000782.5	ENSP00000216862.3
CYP24A1	ENST00000395955.7	c.990+9G>A		intron_variant	Intron 7 of 10	1		ENSP00000379285.3
CYP24A1	ENST00000395954.3	c.564+9G>A		intron_variant	Intron 5 of 9	1		ENSP00000379284.3
CYP24A1	ENST00000487593.1	n.252G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10764 AN: 151438 Hom.: 1277 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0475

GnomAD3 exomes AF: 0.0192 AC: 4830 AN: 251484 Hom.: 540 AF XY: 0.0141 AC XY: 1915 AN XY: 135916

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00783 AC: 11168 AN: 1425738 Hom.: 1162 Cov.: 26 AF XY: 0.00700 AC XY: 4983 AN XY: 711470

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.00405

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000725

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000792

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0713 AC: 10803 AN: 151556 Hom.: 1288 Cov.: 31 AF XY: 0.0691 AC XY: 5114 AN XY: 74062

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.00347

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0470

Alfa AF: 0.0230 Hom.: 443

Bravo AF: 0.0819

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercalcemia, infantile, 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	22
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6022993; hg19: chr20-52779247;