rs2296241

Variant names:

• chr20-54169680-G-A
• rs2296241
• NM_000782.5:c.552C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000782.5(CYP24A1):​c.552C>T​(p.Ala184Ala) 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:9
• Conservation: PhyloP100: -1.60
• Publications: 119 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 -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 VariationId is 338831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000782.5. 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
	CYP24A1	NM_000782.5	MANE Select	c.552C>T	p.Ala184Ala	synonymous	Exon 4 of 12	NP_000773.2	Q07973-1
	CYP24A1	NM_001424340.1		c.552C>T	p.Ala184Ala	synonymous	Exon 4 of 12	NP_001411269.1	Q07973-1
	CYP24A1	NM_001424341.1		c.552C>T	p.Ala184Ala	synonymous	Exon 4 of 12	NP_001411270.1	Q07973-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP24A1	ENST00000216862.8	TSL:1 MANE Select	c.552C>T	p.Ala184Ala	synonymous	Exon 4 of 12	ENSP00000216862.3	Q07973-1
	CYP24A1	ENST00000395955.7	TSL:1	c.552C>T	p.Ala184Ala	synonymous	Exon 4 of 11	ENSP00000379285.3	Q07973-2
	CYP24A1	ENST00000395954.3	TSL:1	c.126C>T	p.Ala42Ala	synonymous	Exon 2 of 10	ENSP00000379284.3	Q07973-3

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

GnomAD2 exomes AF: 0.491 AC: 123351 AN: 251276 AF XY: 0.493

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 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

African (AFR) AF: 0.502 AC: 16802 AN: 33474

American (AMR) AF: 0.398 AC: 17809 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 16295 AN: 26130

East Asian (EAS) AF: 0.439 AC: 17420 AN: 39686

South Asian (SAS) AF: 0.440 AC: 37956 AN: 86256

European-Finnish (FIN) AF: 0.512 AC: 27320 AN: 53324

Middle Eastern (MID) AF: 0.578 AC: 3335 AN: 5766

European-Non Finnish (NFE) AF: 0.530 AC: 589366 AN: 1111890

Other (OTH) AF: 0.526 AC: 31763 AN: 60380

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

African (AFR) AF: 0.500 AC: 20742 AN: 41454

American (AMR) AF: 0.463 AC: 7070 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2175 AN: 3464

East Asian (EAS) AF: 0.408 AC: 2107 AN: 5170

South Asian (SAS) AF: 0.436 AC: 2099 AN: 4814

European-Finnish (FIN) AF: 0.521 AC: 5499 AN: 10552

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 36066 AN: 67974

Other (OTH) AF: 0.523 AC: 1102 AN: 2106

Alfa AF: 0.526 Hom.: 105754

Bravo AF: 0.504

Asia WGS AF: 0.441 AC: 1534 AN: 3478

EpiCase AF: 0.548

EpiControl AF: 0.541

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hypercalcemia, infantile, 1 (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.1
DANN	Benign	0.70
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2296241; hg19: chr20-52786219; COSMIC: COSV53773614; COSMIC: COSV53773614;