Genetic Variant CYP24A1:p.Arg157Gln (chr20-54171650-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000782.5(CYP24A1):c.470G>A(p.Arg157Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,613,850 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R157W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 61 hom. )

Consequence

CYP24A1
NM_000782.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 7.27

Publications

18 publications found

Variant links:

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

CYP24A1 links:

ENSG00000286587 (HGNC:):

ENSG00000286587 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000782.5

BP4

Computational evidence support a benign effect (MetaRNN=0.01509133).

BP6

Variant 20-54171650-C-T is Benign according to our data. Variant chr20-54171650-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 634948.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00368 (560/152168) while in subpopulation NFE AF = 0.00703 (478/68006). AF 95% confidence interval is 0.00651. There are 4 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP24A1	NM_000782.5	MANE Select	c.470G>A	p.Arg157Gln	missense	Exon 3 of 12	NP_000773.2	Q07973-1
CYP24A1	NM_001424340.1		c.470G>A	p.Arg157Gln	missense	Exon 3 of 12	NP_001411269.1	Q07973-1
CYP24A1	NM_001424341.1		c.470G>A	p.Arg157Gln	missense	Exon 3 of 12	NP_001411270.1	Q07973-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP24A1	ENST00000216862.8	TSL:1 MANE Select	c.470G>A	p.Arg157Gln	missense	Exon 3 of 12	ENSP00000216862.3	Q07973-1
CYP24A1	ENST00000395955.7	TSL:1	c.470G>A	p.Arg157Gln	missense	Exon 3 of 11	ENSP00000379285.3	Q07973-2
CYP24A1	ENST00000395954.3	TSL:1	c.44G>A	p.Arg15Gln	missense	Exon 1 of 10	ENSP00000379284.3	Q07973-3

Frequencies

GnomAD3 genomes

AF:

0.00368

AC:

560

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00296

AC:

744

AN:

251282

AF XY:

0.00297

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00653

AC:

9546

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

4505

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33472

American (AMR)

AF:

0.000738

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000393

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00806

AC:

8964

AN:

1111858

Other (OTH)

AF:

0.00659

AC:

398

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

687

1374

2062

2749

3436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

362

724

1086

1448

1810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00368

AC:

560

AN:

152168

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

251

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00145

AC:

AN:

41504

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00703

AC:

478

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00545

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00251

AC:

305

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00664

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hypercalcemia, infantile, 1 (2)

CYP24A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.027

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.8

PhyloP100

7.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

REVEL

Benign

0.20

Sift

Benign

0.14

Sift4G

Benign

0.084

Polyphen

0.72

Vest4

0.86

MVP

0.78

MPC

0.11

ClinPred

0.023

GERP RS

4.4

PromoterAI

0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.47

gMVP

0.81

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over