rs6022993

Variant names:

• chr20-54162708-C-T
• rs6022993
• NM_000782.5:c.990+9G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_000782.5(CYP24A1):​c.990+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,577,294 control chromosomes in the GnomAD database, including 2,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (1288 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (1162 hom.)
• Consequence: CYP24A1 NM_000782.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0790
• 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 20-54162708-C-T is Benign according to our data. Variant chr20-54162708-C-T is described in ClinVar as Benign. ClinVar VariationId is 338821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP24A1	NM_000782.5	MANE Select	c.990+9G>A		intron	N/A	NP_000773.2
	CYP24A1	NM_001424340.1		c.990+9G>A		intron	N/A	NP_001411269.1
	CYP24A1	NM_001424341.1		c.990+9G>A		intron	N/A	NP_001411270.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP24A1	ENST00000216862.8	TSL:1 MANE Select	c.990+9G>A		intron	N/A	ENSP00000216862.3
	CYP24A1	ENST00000395955.7	TSL:1	c.990+9G>A		intron	N/A	ENSP00000379285.3
	CYP24A1	ENST00000395954.3	TSL:1	c.564+9G>A		intron	N/A	ENSP00000379284.3

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10764 AN: 151438 Hom.: 1277 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0475

GnomAD2 exomes AF: 0.0192 AC: 4830 AN: 251484 AF XY: 0.0141

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00783 AC: 11168 AN: 1425738 Hom.: 1162 Cov.: 26 AF XY: 0.00700 AC XY: 4983 AN XY: 711470

African (AFR) AF: 0.259 AC: 8425 AN: 32504

American (AMR) AF: 0.0135 AC: 602 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00405 AC: 105 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.000725 AC: 62 AN: 85518

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.0165 AC: 94 AN: 5684

European-Non Finnish (NFE) AF: 0.000792 AC: 855 AN: 1079256

Other (OTH) AF: 0.0173 AC: 1024 AN: 59216

GnomAD4 genome AF: 0.0713 AC: 10803 AN: 151556 Hom.: 1288 Cov.: 31 AF XY: 0.0691 AC XY: 5114 AN XY: 74062

African (AFR) AF: 0.248 AC: 10204 AN: 41124

American (AMR) AF: 0.0262 AC: 399 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 12 AN: 3462

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 67930

Other (OTH) AF: 0.0470 AC: 99 AN: 2108

Alfa AF: 0.0298 Hom.: 782

Bravo AF: 0.0819

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	22
DANN	Benign	0.69
PhyloP100		-0.079
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6022993; hg19: chr20-52779247;