rs2762934

Variant names:

• chr20-54154722-G-A
• rs2762934
• NM_000782.5:c.*50C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000782.5(CYP24A1):​c.*50C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 153,476 control chromosomes in the GnomAD database, including 2,635 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2594 hom., cov: 29)
  • Exomes 𝑓: 0.21 (41 hom.)
• Consequence: CYP24A1 NM_000782.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.100
• Publications: 50 publications found

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]

CYP24A1 Gene-Disease associations (from GenCC):

• hypercalcemia, infantile, 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal recessive infantile hypercalcemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286587 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.*50C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.*50C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27460 AN: 151716 Hom.: 2597 Cov.: 29

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.215 AC: 353 AN: 1642 Hom.: 41 Cov.: 0 AF XY: 0.214 AC XY: 185 AN XY: 866

African (AFR) AF: 0.206 AC: 7 AN: 34

American (AMR) AF: 0.114 AC: 5 AN: 44

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 14 AN: 56

East Asian (EAS) AF: 0.131 AC: 26 AN: 198

South Asian (SAS) AF: 0.500 AC: 6 AN: 12

European-Finnish (FIN) AF: 0.263 AC: 59 AN: 224

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.225 AC: 225 AN: 1000

Other (OTH) AF: 0.139 AC: 10 AN: 72

GnomAD4 genome AF: 0.181 AC: 27471 AN: 151834 Hom.: 2594 Cov.: 29 AF XY: 0.185 AC XY: 13716 AN XY: 74176

African (AFR) AF: 0.162 AC: 6728 AN: 41420

American (AMR) AF: 0.157 AC: 2393 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3464

East Asian (EAS) AF: 0.101 AC: 522 AN: 5168

South Asian (SAS) AF: 0.292 AC: 1403 AN: 4804

European-Finnish (FIN) AF: 0.232 AC: 2436 AN: 10492

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12572 AN: 67948

Other (OTH) AF: 0.196 AC: 412 AN: 2098

Alfa AF: 0.183 Hom.: 9292

Bravo AF: 0.172

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.1
DANN	Benign	0.71
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2762934; hg19: chr20-52771261;