rs2296241

chr20-54169680-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000782.5(CYP24A1):c.552C>T(p.Ala184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,638 control chromosomes in the GnomAD database, including 218,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19925 hom., cov: 33)
  • Exomes 𝑓: 0.52 (198132 hom.)
• Consequence: CYP24A1 NM_000782.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.60

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 20-54169680-G-A is Benign according to our data. Variant chr20-54169680-G-A is described in ClinVar as [Benign]. Clinvar id is 338831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54169680-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP24A1	NM_000782.5	c.552C>T	p.Ala184=	synonymous_variant	4/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8	c.552C>T	p.Ala184=	synonymous_variant	4/12	1	NM_000782.5	P1
CYP24A1	ENST00000395955.7	c.552C>T	p.Ala184=	synonymous_variant	4/11	1
CYP24A1	ENST00000395954.3	c.126C>T	p.Ala42=	synonymous_variant	2/10	1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77391 AN: 151898 Hom.: 19911 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.491 AC: 123351 AN: 251276 Hom.: 30995 AF XY: 0.493 AC XY: 66951 AN XY: 135838

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.622

Gnomad EAS exome AF: 0.419

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.519 AC: 758066 AN: 1461622 Hom.: 198132 Cov.: 106 AF XY: 0.518 AC XY: 376380 AN XY: 727124

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.624

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.440

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.530

Gnomad4 OTH exome AF: 0.526

GnomAD4 genome AF: 0.509 AC: 77450 AN: 152016 Hom.: 19925 Cov.: 33 AF XY: 0.506 AC XY: 37623 AN XY: 74290

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.523

Alfa AF: 0.529 Hom.: 55654

Bravo AF: 0.504

Asia WGS AF: 0.441 AC: 1534 AN: 3478

EpiCase AF: 0.548

EpiControl AF: 0.541

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercalcemia, infantile, 1 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 06, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ala184Ala in exon 4 of CYP24A1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 53.00% (35334/6666 8) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs2296241). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.1
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2296241; hg19: chr20-52786219; COSMIC: COSV53773614; COSMIC: COSV53773614;