rs387907324

Positions:

chr20-54162743-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000782.5(CYP24A1):c.964G>A(p.Glu322Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,602,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CYP24A1
NM_000782.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.16

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 20-54162743-C-T is Pathogenic according to our data. Variant chr20-54162743-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29681.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-54162743-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP24A1	NM_000782.5 linkuse as main transcript	c.964G>A	p.Glu322Lys	missense_variant	7/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8 linkuse as main transcript	c.964G>A	p.Glu322Lys	missense_variant	7/12	1	NM_000782.5	P1	Q07973-1
CYP24A1	ENST00000395955.7 linkuse as main transcript	c.964G>A	p.Glu322Lys	missense_variant	7/11	1			Q07973-2
CYP24A1	ENST00000395954.3 linkuse as main transcript	c.538G>A	p.Glu180Lys	missense_variant	5/10	1			Q07973-3
CYP24A1	ENST00000487593.1 linkuse as main transcript	n.217G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251490

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1450314

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

722424

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000218

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000316

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercalcemia, infantile, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 03, 2011

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 322 of the CYP24A1 protein (p.Glu322Lys). This variant is present in population databases (rs387907324, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYP24A1 function (PMID: 21675912). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP24A1 protein function. ClinVar contains an entry for this variant (Variation ID: 29681). This missense change has been observed in individual(s) with clinical features of CYP24A1-related conditions (PMID: 21675912, 28470390, 33099630, 34307984, 34662328). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.4

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MutPred

0.87

Gain of ubiquitination at E322 (P = 0.0452);Gain of ubiquitination at E322 (P = 0.0452);.;

MVP

0.89

MPC

0.40

ClinPred

0.98

GERP RS

5.6

Varity_R

0.98

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over