20-54171651-G-T

Variant names:

• chr20-54171651-G-T
• rs35873579
• NM_000782.5:c.469C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000782.5(CYP24A1):​c.469C>A​(p.Arg157Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,613,754 control chromosomes in the GnomAD database, including 486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.023 (458 hom.)
• Consequence: CYP24A1 NM_000782.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.42
• Publications: 22 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=-0.56).
• BP6: Variant 20-54171651-G-T is Benign according to our data. Variant chr20-54171651-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 895614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2458/152092) while in subpopulation NFE AF = 0.0228 (1549/68004). AF 95% confidence interval is 0.0218. There are 28 homozygotes in GnomAd4. There are 1110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

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.469C>A	p.Arg157Arg	synonymous	Exon 3 of 12	NP_000773.2	Q07973-1
	CYP24A1	NM_001424340.1		c.469C>A	p.Arg157Arg	synonymous	Exon 3 of 12	NP_001411269.1	Q07973-1
	CYP24A1	NM_001424341.1		c.469C>A	p.Arg157Arg	synonymous	Exon 3 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.469C>A	p.Arg157Arg	synonymous	Exon 3 of 12	ENSP00000216862.3	Q07973-1
	CYP24A1	ENST00000395955.7	TSL:1	c.469C>A	p.Arg157Arg	synonymous	Exon 3 of 11	ENSP00000379285.3	Q07973-2
	CYP24A1	ENST00000395954.3	TSL:1	c.43C>A	p.Arg15Arg	synonymous	Exon 1 of 10	ENSP00000379284.3	Q07973-3

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2445 AN: 151974 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00699

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0163 AC: 4105 AN: 251288 AF XY: 0.0174

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0230 AC: 33549 AN: 1461662 Hom.: 458 Cov.: 33 AF XY: 0.0228 AC XY: 16601 AN XY: 727144

African (AFR) AF: 0.00807 AC: 270 AN: 33472

American (AMR) AF: 0.0142 AC: 634 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 772 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0177 AC: 1525 AN: 86250

European-Finnish (FIN) AF: 0.00292 AC: 156 AN: 53410

Middle Eastern (MID) AF: 0.0335 AC: 193 AN: 5762

European-Non Finnish (NFE) AF: 0.0256 AC: 28473 AN: 1111844

Other (OTH) AF: 0.0253 AC: 1525 AN: 60376

GnomAD4 genome AF: 0.0162 AC: 2458 AN: 152092 Hom.: 28 Cov.: 32 AF XY: 0.0149 AC XY: 1110 AN XY: 74356

African (AFR) AF: 0.00726 AC: 301 AN: 41450

American (AMR) AF: 0.0183 AC: 280 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0154 AC: 74 AN: 4800

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1549 AN: 68004

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.00691 Hom.: 80

Bravo AF: 0.0174

EpiCase AF: 0.0268

EpiControl AF: 0.0257

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.8
DANN	Benign	0.66
PhyloP100		1.4
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35873579; hg19: chr20-52788190; COSMIC: COSV53775925; COSMIC: COSV53775925;