rs2279357

Positions:

• chr15-74338282-T-C
• chr15-74338282-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000781.3(CYP11A1):​c.1435-179A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 759,048 control chromosomes in the GnomAD database, including 178,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35634 hom., cov: 31)
  • Exomes 𝑓: 0.68 (142418 hom.)
• Consequence: CYP11A1 NM_000781.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.134

Genes affected

CYP11A1 (HGNC:2590): (cytochrome P450 family 11 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 protein localizes to the mitochondrial inner membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in the synthesis of the steroid hormones. Two transcript variants encoding different isoforms have been found for this gene. The cellular location of the smaller isoform is unclear since it lacks the mitochondrial-targeting transit peptide. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-74338282-T-C is Benign according to our data. Variant chr15-74338282-T-C is described in ClinVar as [Benign]. Clinvar id is 1295294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.1435-179A>G		intron_variant		ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.961-179A>G		intron_variant			NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.1435-179A>G		intron_variant		1	NM_000781.3	ENSP00000268053	P1
CYP11A1	ENST00000358632.8	c.961-179A>G		intron_variant		2		ENSP00000351455
CYP11A1	ENST00000435365.5	c.*111-179A>G		intron_variant, NMD_transcript_variant		3		ENSP00000391081
CYP11A1	ENST00000498141.1	n.528+38A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103937 AN: 151890 Hom.: 35620 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.710

Gnomad OTH AF: 0.663

GnomAD4 exome AF: 0.681 AC: 413307 AN: 607038 Hom.: 142418 Cov.: 8 AF XY: 0.675 AC XY: 216283 AN XY: 320416

Gnomad4 AFR exome AF: 0.665

Gnomad4 AMR exome AF: 0.653

Gnomad4 ASJ exome AF: 0.657

Gnomad4 EAS exome AF: 0.531

Gnomad4 SAS exome AF: 0.568

Gnomad4 FIN exome AF: 0.757

Gnomad4 NFE exome AF: 0.708

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.684 AC: 103992 AN: 152010 Hom.: 35634 Cov.: 31 AF XY: 0.682 AC XY: 50659 AN XY: 74312

Gnomad4 AFR AF: 0.663

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.669

Gnomad4 EAS AF: 0.549

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.761

Gnomad4 NFE AF: 0.710

Gnomad4 OTH AF: 0.656

Alfa AF: 0.697 Hom.: 19788

Bravo AF: 0.680

Asia WGS AF: 0.501 AC: 1742 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.3
DANN	Benign	0.54

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

LitVar

Other links and lift over

dbSNP: rs2279357; hg19: chr15-74630623; COSMIC: COSV51435767; COSMIC: COSV51435767;