rs2296239

chr20-54158989-C-T

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.1125G>A(p.Pro375=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,812 control chromosomes in the GnomAD database, including 53,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7345 hom., cov: 33)
  • Exomes 𝑓: 0.24 (46503 hom.)
• Consequence: CYP24A1 NM_000782.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.32

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=-0.64).
• BP6: Variant 20-54158989-C-T is Benign according to our data. Variant chr20-54158989-C-T is described in ClinVar as [Benign]. Clinvar id is 338815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54158989-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP24A1	NM_000782.5	c.1125G>A	p.Pro375=	synonymous_variant	8/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8	c.1125G>A	p.Pro375=	synonymous_variant	8/12	1	NM_000782.5	P1
CYP24A1	ENST00000395955.7	c.1125G>A	p.Pro375=	synonymous_variant	8/11	1
CYP24A1	ENST00000395954.3	c.699G>A	p.Pro233=	synonymous_variant	6/10	1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44189 AN: 151934 Hom.: 7338 Cov.: 33

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.264

GnomAD3 exomes AF: 0.279 AC: 70250 AN: 251420 Hom.: 11550 AF XY: 0.277 AC XY: 37595 AN XY: 135884

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.615

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.240 AC: 350135 AN: 1461760 Hom.: 46503 Cov.: 34 AF XY: 0.241 AC XY: 175352 AN XY: 727192

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.592

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.291 AC: 44218 AN: 152052 Hom.: 7345 Cov.: 33 AF XY: 0.294 AC XY: 21824 AN XY: 74326

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.606

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.265

Alfa AF: 0.231 Hom.: 10168

Bravo AF: 0.300

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypercalcemia, infantile, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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	-0.64
Cadd	Benign	0.17
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2296239; hg19: chr20-52775528; COSMIC: COSV53777047; COSMIC: COSV53777047;