rs2279357

Variant names:

• chr15-74338282-T-C
• rs2279357
• NM_000781.3:c.1435-179A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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]

CYP11A1 Gene-Disease associations (from GenCC):

• Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CYP11A1	NM_000781.3	c.1435-179A>G		intron_variant	Intron 8 of 8	ENST00000268053.11	NP_000772.2
CYP11A1	NM_001099773.2	c.961-179A>G		intron_variant	Intron 8 of 8		NP_001093243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11A1	ENST00000268053.11	c.1435-179A>G		intron_variant	Intron 8 of 8	1	NM_000781.3	ENSP00000268053.6
CYP11A1	ENST00000358632.8	c.961-179A>G		intron_variant	Intron 8 of 8	2		ENSP00000351455.4
CYP11A1	ENST00000435365.5	n.*111-179A>G		intron_variant	Intron 7 of 7	3		ENSP00000391081.1
CYP11A1	ENST00000498141.1	n.528+38A>G		intron_variant	Intron 2 of 2	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

African (AFR) AF: 0.665 AC: 11051 AN: 16608

American (AMR) AF: 0.653 AC: 21236 AN: 32506

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 11721 AN: 17832

East Asian (EAS) AF: 0.531 AC: 17091 AN: 32198

South Asian (SAS) AF: 0.568 AC: 32879 AN: 57926

European-Finnish (FIN) AF: 0.757 AC: 26221 AN: 34642

Middle Eastern (MID) AF: 0.642 AC: 1601 AN: 2494

European-Non Finnish (NFE) AF: 0.708 AC: 269860 AN: 381028

Other (OTH) AF: 0.681 AC: 21647 AN: 31804

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

African (AFR) AF: 0.663 AC: 27487 AN: 41434

American (AMR) AF: 0.674 AC: 10302 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2324 AN: 3472

East Asian (EAS) AF: 0.549 AC: 2827 AN: 5150

South Asian (SAS) AF: 0.548 AC: 2639 AN: 4814

European-Finnish (FIN) AF: 0.761 AC: 8067 AN: 10598

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.710 AC: 48276 AN: 67956

Other (OTH) AF: 0.656 AC: 1381 AN: 2104

Alfa AF: 0.697 Hom.: 21854

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

Aug 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.3
DANN	Benign	0.54
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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