20-54164712-G-C

Variant names:

• chr20-54164712-G-C
• rs2762939
• NM_000782.5:c.733-149C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000782.5(CYP24A1):​c.733-149C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,476,674 control chromosomes in the GnomAD database, including 60,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10483 hom., cov: 31)
  • Exomes 𝑓: 0.27 (49827 hom.)
• Consequence: CYP24A1 NM_000782.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.28
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-54164712-G-C is Benign according to our data. Variant chr20-54164712-G-C is described in ClinVar as Benign. ClinVar VariationId is 1297888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.733-149C>G		intron_variant	Intron 5 of 11	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.733-149C>G		intron_variant	Intron 5 of 11	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52667 AN: 151676 Hom.: 10454 Cov.: 31

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.317

GnomAD4 exome AF: 0.266 AC: 352256 AN: 1324880 Hom.: 49827 AF XY: 0.267 AC XY: 175319 AN XY: 656012

African (AFR) AF: 0.566 AC: 17198 AN: 30392

American (AMR) AF: 0.203 AC: 7198 AN: 35384

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 6275 AN: 24258

East Asian (EAS) AF: 0.244 AC: 8560 AN: 35022

South Asian (SAS) AF: 0.340 AC: 26185 AN: 76978

European-Finnish (FIN) AF: 0.311 AC: 11244 AN: 36150

Middle Eastern (MID) AF: 0.306 AC: 1382 AN: 4512

European-Non Finnish (NFE) AF: 0.252 AC: 258436 AN: 1026620

Other (OTH) AF: 0.284 AC: 15778 AN: 55564

GnomAD4 genome AF: 0.347 AC: 52727 AN: 151794 Hom.: 10483 Cov.: 31 AF XY: 0.348 AC XY: 25840 AN XY: 74150

African (AFR) AF: 0.559 AC: 23118 AN: 41354

American (AMR) AF: 0.258 AC: 3940 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 907 AN: 3470

East Asian (EAS) AF: 0.247 AC: 1275 AN: 5164

South Asian (SAS) AF: 0.337 AC: 1614 AN: 4796

European-Finnish (FIN) AF: 0.336 AC: 3524 AN: 10494

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17357 AN: 67944

Other (OTH) AF: 0.323 AC: 682 AN: 2110

Alfa AF: 0.154 Hom.: 286

Bravo AF: 0.348

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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	-0.91
CADD	Benign	0.052
DANN	Benign	0.40
PhyloP100		-3.3
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: rs2762939; hg19: chr20-52781251;