NM_000782.5:c.1125G>A

Variant names:

• chr20-54158989-C-T
• rs2296239
• NM_000782.5:c.1125G>A

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.1125G>A​(p.Pro375Pro) 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:7
• Conservation: PhyloP100: -3.32
• Publications: 35 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=-0.64).
• BP6: Variant 20-54158989-C-T is Benign according to our data. Variant chr20-54158989-C-T is described in ClinVar as Benign. ClinVar VariationId is 338815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1125G>A	p.Pro375Pro	synonymous	Exon 8 of 12	NP_000773.2
	CYP24A1	NM_001424340.1		c.1125G>A	p.Pro375Pro	synonymous	Exon 8 of 12	NP_001411269.1
	CYP24A1	NM_001424341.1		c.1125G>A	p.Pro375Pro	synonymous	Exon 8 of 12	NP_001411270.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP24A1	ENST00000216862.8	TSL:1 MANE Select	c.1125G>A	p.Pro375Pro	synonymous	Exon 8 of 12	ENSP00000216862.3
	CYP24A1	ENST00000395955.7	TSL:1	c.1125G>A	p.Pro375Pro	synonymous	Exon 8 of 11	ENSP00000379285.3
	CYP24A1	ENST00000395954.3	TSL:1	c.699G>A	p.Pro233Pro	synonymous	Exon 6 of 10	ENSP00000379284.3

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

GnomAD2 exomes AF: 0.279 AC: 70250 AN: 251420 AF XY: 0.277

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 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

African (AFR) AF: 0.425 AC: 14228 AN: 33478

American (AMR) AF: 0.270 AC: 12056 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6117 AN: 26134

East Asian (EAS) AF: 0.592 AC: 23482 AN: 39688

South Asian (SAS) AF: 0.341 AC: 29376 AN: 86252

European-Finnish (FIN) AF: 0.208 AC: 11113 AN: 53404

Middle Eastern (MID) AF: 0.209 AC: 1206 AN: 5768

European-Non Finnish (NFE) AF: 0.213 AC: 236562 AN: 1111922

Other (OTH) AF: 0.265 AC: 15995 AN: 60390

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

African (AFR) AF: 0.417 AC: 17277 AN: 41458

American (AMR) AF: 0.274 AC: 4181 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3468

East Asian (EAS) AF: 0.606 AC: 3134 AN: 5168

South Asian (SAS) AF: 0.354 AC: 1706 AN: 4820

European-Finnish (FIN) AF: 0.204 AC: 2152 AN: 10552

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14217 AN: 67980

Other (OTH) AF: 0.265 AC: 561 AN: 2114

Alfa AF: 0.241 Hom.: 16599

Bravo AF: 0.300

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.17
DANN	Benign	0.49
PhyloP100		-3.3
Mutation Taster		=81/19	polymorphism

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: rs2296239; hg19: chr20-52775528; COSMIC: COSV53777047; COSMIC: COSV53777047;