chr20-54165899-T-G

Variant names:

• chr20-54165899-T-G
• rs4809958
• NM_000782.5:c.641-66A>C

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.641-66A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 890,584 control chromosomes in the GnomAD database, including 14,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1845 hom., cov: 33)
  • Exomes 𝑓: 0.17 (12169 hom.)
• Consequence: CYP24A1 NM_000782.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.311
• Publications: 32 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=-0.8).
• BP6: Variant 20-54165899-T-G is Benign according to our data. Variant chr20-54165899-T-G is described in ClinVar as Benign. ClinVar VariationId is 1252890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.357 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.641-66A>C		intron	N/A	NP_000773.2
	CYP24A1	NM_001424340.1		c.641-66A>C		intron	N/A	NP_001411269.1
	CYP24A1	NM_001424341.1		c.641-66A>C		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.641-66A>C		intron	N/A	ENSP00000216862.3
	CYP24A1	ENST00000395955.7	TSL:1	c.641-66A>C		intron	N/A	ENSP00000379285.3
	CYP24A1	ENST00000395954.3	TSL:1	c.215-66A>C		intron	N/A	ENSP00000379284.3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21495 AN: 152114 Hom.: 1843 Cov.: 33

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.172 AC: 126686 AN: 738352 Hom.: 12169 AF XY: 0.173 AC XY: 68206 AN XY: 393420

African (AFR) AF: 0.0694 AC: 1400 AN: 20166

American (AMR) AF: 0.147 AC: 6411 AN: 43724

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3368 AN: 21590

East Asian (EAS) AF: 0.389 AC: 14226 AN: 36568

South Asian (SAS) AF: 0.197 AC: 14165 AN: 71750

European-Finnish (FIN) AF: 0.143 AC: 7379 AN: 51422

Middle Eastern (MID) AF: 0.156 AC: 680 AN: 4354

European-Non Finnish (NFE) AF: 0.162 AC: 73102 AN: 452112

Other (OTH) AF: 0.162 AC: 5955 AN: 36666

GnomAD4 genome AF: 0.141 AC: 21502 AN: 152232 Hom.: 1845 Cov.: 33 AF XY: 0.142 AC XY: 10588 AN XY: 74430

African (AFR) AF: 0.0691 AC: 2870 AN: 41540

American (AMR) AF: 0.140 AC: 2140 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3470

East Asian (EAS) AF: 0.371 AC: 1924 AN: 5182

South Asian (SAS) AF: 0.211 AC: 1018 AN: 4820

European-Finnish (FIN) AF: 0.134 AC: 1419 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11113 AN: 68002

Other (OTH) AF: 0.140 AC: 296 AN: 2116

Alfa AF: 0.153 Hom.: 6654

Bravo AF: 0.139

Asia WGS AF: 0.247 AC: 856 AN: 3478

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 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.69
DANN	Benign	0.82
PhyloP100		0.31
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: rs4809958; hg19: chr20-52782438; COSMIC: COSV107247186; COSMIC: COSV107247186;