rs6161

Variant names:

• chr15-74343027-C-T
• rs6161
• NM_000781.3:c.940G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-74343027-C-T
• chr15-74343027-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000781.3(CYP11A1):​c.940G>A​(p.Glu314Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,613,102 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: CYP11A1 NM_000781.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3 B:3
• Conservation: PhyloP100: 1.95
• Publications: 37 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: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011359721).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00248 (378/152302) while in subpopulation NFE AF = 0.00422 (287/68022). AF 95% confidence interval is 0.00382. There are 1 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000781.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	NM_000781.3	MANE Select	c.940G>A	p.Glu314Lys	missense	Exon 5 of 9	NP_000772.2	P05108-1
	CYP11A1	NM_001099773.2		c.466G>A	p.Glu156Lys	missense	Exon 5 of 9	NP_001093243.1	P05108-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	ENST00000268053.11	TSL:1 MANE Select	c.940G>A	p.Glu314Lys	missense	Exon 5 of 9	ENSP00000268053.6	P05108-1
	CYP11A1	ENST00000950903.1		c.940G>A	p.Glu314Lys	missense	Exon 5 of 10	ENSP00000620962.1
	CYP11A1	ENST00000950905.1		c.940G>A	p.Glu314Lys	missense	Exon 5 of 9	ENSP00000620964.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00253 AC: 636 AN: 251458 AF XY: 0.00263

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00404 AC: 5906 AN: 1460800 Hom.: 17 Cov.: 32 AF XY: 0.00398 AC XY: 2895 AN XY: 726720

African (AFR) AF: 0.000807 AC: 27 AN: 33438

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00167 AC: 144 AN: 86198

European-Finnish (FIN) AF: 0.00243 AC: 130 AN: 53410

Middle Eastern (MID) AF: 0.00122 AC: 6 AN: 4918

European-Non Finnish (NFE) AF: 0.00483 AC: 5375 AN: 1111974

Other (OTH) AF: 0.00313 AC: 189 AN: 60302

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74470

African (AFR) AF: 0.000938 AC: 39 AN: 41558

American (AMR) AF: 0.000588 AC: 9 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00344 Hom.: 17

Bravo AF: 0.00221

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00338 AC: 29

ExAC AF: 0.00242 AC: 294

EpiCase AF: 0.00387

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	2	Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency (7)
2	-	-	not provided (2)
-	1	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)
1	-	-	Congenital adrenal hyperplasia (1)
1	-	-	CYP11A1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.30	N
PhyloP100		1.9
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Benign	0.34	T
Polyphen		0.063	B
Vest4		0.31
MVP		0.79
MPC		0.41
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.55
gMVP		0.55
Mutation Taster		=70/30	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs6161; hg19: chr15-74635368; COSMIC: COSV51430586; COSMIC: COSV51430586;