rs6091828

Variant names:

• chr20-54162671-G-T
• rs6091828
• NM_000782.5:c.990+46C>A

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.990+46C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,222,902 control chromosomes in the GnomAD database, including 1,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (612 hom., cov: 30)
  • Exomes 𝑓: 0.039 (1348 hom.)
• Consequence: CYP24A1 NM_000782.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0480
• Publications: 4 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=-0.93).
• BP6: Variant 20-54162671-G-T is Benign according to our data. Variant chr20-54162671-G-T is described in ClinVar as Benign. ClinVar VariationId is 1174391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.990+46C>A		intron_variant	Intron 7 of 11	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.990+46C>A		intron_variant	Intron 7 of 11	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10485 AN: 147782 Hom.: 609 Cov.: 30

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0519

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0707

GnomAD2 exomes AF: 0.0559 AC: 14037 AN: 251292 AF XY: 0.0553

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0949

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0462

GnomAD4 exome AF: 0.0386 AC: 41484 AN: 1075004 Hom.: 1348 Cov.: 15 AF XY: 0.0402 AC XY: 22213 AN XY: 552892

African (AFR) AF: 0.149 AC: 3726 AN: 24976

American (AMR) AF: 0.0912 AC: 4026 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 875 AN: 23634

East Asian (EAS) AF: 0.0231 AC: 856 AN: 37114

South Asian (SAS) AF: 0.0984 AC: 7724 AN: 78472

European-Finnish (FIN) AF: 0.0364 AC: 1930 AN: 53006

Middle Eastern (MID) AF: 0.0493 AC: 247 AN: 5012

European-Non Finnish (NFE) AF: 0.0263 AC: 20003 AN: 761196

Other (OTH) AF: 0.0442 AC: 2097 AN: 47468

GnomAD4 genome AF: 0.0711 AC: 10513 AN: 147898 Hom.: 612 Cov.: 30 AF XY: 0.0735 AC XY: 5304 AN XY: 72152

African (AFR) AF: 0.146 AC: 5852 AN: 40082

American (AMR) AF: 0.0880 AC: 1297 AN: 14732

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 156 AN: 3408

East Asian (EAS) AF: 0.0312 AC: 151 AN: 4842

South Asian (SAS) AF: 0.113 AC: 519 AN: 4588

European-Finnish (FIN) AF: 0.0406 AC: 416 AN: 10252

Middle Eastern (MID) AF: 0.0490 AC: 14 AN: 286

European-Non Finnish (NFE) AF: 0.0280 AC: 1866 AN: 66756

Other (OTH) AF: 0.0733 AC: 151 AN: 2060

Alfa AF: 0.0464 Hom.: 522

Bravo AF: 0.0763

Asia WGS AF: 0.104 AC: 363 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.53
PhyloP100		-0.048
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: rs6091828; hg19: chr20-52779210; COSMIC: COSV53774592;