dbSNP rs6127118: CYP24A1:c.990+204C>T (chr20-54162513-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000782.5(CYP24A1):c.990+204C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000613 in 136,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00064 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CYP24A1
NM_000782.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.94

Publications

10 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5 link	c.990+204C>T		intron_variant	Intron 7 of 11	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8 link	c.990+204C>T		intron_variant	Intron 7 of 11	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes

AF:

0.000614

AC:

AN:

136828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000662

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00225

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.000540

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000285

Gnomad OTH

AF:

0.00164

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000645

AC:

236

AN:

366058

Hom.:

AF XY:

0.000615

AC XY:

119

AN XY:

193612

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000376

AC:

AN:

10640

American (AMR)

AF:

0.00170

AC:

AN:

17630

Ashkenazi Jewish (ASJ)

AF:

0.000698

AC:

AN:

11466

East Asian (EAS)

AF:

0.00158

AC:

AN:

21498

South Asian (SAS)

AF:

0.000355

AC:

AN:

42216

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

21296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1618

European-Non Finnish (NFE)

AF:

0.000586

AC:

128

AN:

218608

Other (OTH)

AF:

0.000522

AC:

AN:

21086

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000613

AC:

AN:

136924

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

AN XY:

66112

show subpopulations

African (AFR)

AF:

0.000660

AC:

AN:

36352

American (AMR)

AF:

0.00133

AC:

AN:

13488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3244

East Asian (EAS)

AF:

0.00226

AC:

AN:

4432

South Asian (SAS)

AF:

0.00149

AC:

AN:

4020

European-Finnish (FIN)

AF:

0.000540

AC:

AN:

9260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000285

AC:

AN:

63164

Other (OTH)

AF:

0.00162

AC:

AN:

1852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.166

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.39

(source)

DANN

Benign

0.75

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over