rs6068816

Positions:

• chr20-54164552-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000782.5(CYP24A1):​c.744G>A​(p.Thr248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,614,026 control chromosomes in the GnomAD database, including 12,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (1008 hom., cov: 32)
  • Exomes 𝑓: 0.11 (11261 hom.)
• Consequence: CYP24A1 NM_000782.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.32

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 20-54164552-C-T is Benign according to our data. Variant chr20-54164552-C-T is described in ClinVar as [Benign]. Clinvar id is 338825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-54164552-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.744G>A	p.Thr248=	synonymous_variant	6/12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.744G>A	p.Thr248=	synonymous_variant	6/12	1	NM_000782.5	ENSP00000216862	P1
CYP24A1	ENST00000395955.7	c.744G>A	p.Thr248=	synonymous_variant	6/11	1		ENSP00000379285
CYP24A1	ENST00000395954.3	c.318G>A	p.Thr106=	synonymous_variant	4/10	1		ENSP00000379284
CYP24A1	ENST00000487593.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0948 AC: 14411 AN: 152056 Hom.: 1007 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0967

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.124 AC: 31139 AN: 251404 Hom.: 2613 AF XY: 0.126 AC XY: 17137 AN XY: 135896

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.367

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.0734

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.113 AC: 165407 AN: 1461852 Hom.: 11261 Cov.: 33 AF XY: 0.115 AC XY: 83343 AN XY: 727230

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.0760

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.0947 AC: 14415 AN: 152174 Hom.: 1008 Cov.: 32 AF XY: 0.0958 AC XY: 7129 AN XY: 74380

Gnomad4 AFR AF: 0.0408

Gnomad4 AMR AF: 0.0969

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.0652

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.103

Alfa AF: 0.107 Hom.: 2037

Bravo AF: 0.0945

EpiCase AF: 0.100

EpiControl AF: 0.110

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypercalcemia, infantile, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.23
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs6068816; hg19: chr20-52781091;