rs61752794

Positions:

• chr8-142875332-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000519285.5(CYP11B1):​c.136A>G​(p.Met46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,575,564 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M46T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (18 hom., cov: 32)
  • Exomes 𝑓: 0.010 (88 hom.)
• Consequence: CYP11B1 ENST00000519285.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.86

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B 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 is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

GML (HGNC:4375): (glycosylphosphatidylinositol anchored molecule like) Predicted to be involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; apoptotic process; and negative regulation of cell population proliferation. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036462545).
• BP6: Variant 8-142875332-T-C is Benign according to our data. Variant chr8-142875332-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35984.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0164 (2295/139844) while in subpopulation AFR AF= 0.0222 (893/40174). AF 95% confidence interval is 0.021. There are 18 homozygotes in gnomad4. There are 1143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.1122-20A>G		intron_variant		ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.1122-20A>G		intron_variant			NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1122-20A>G		intron_variant		1	NM_000497.4	ENSP00000292427	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2299 AN: 139734 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.0138

Gnomad AMR AF: 0.00830

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00668

Gnomad SAS AF: 0.0148

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0142

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00938 AC: 2208 AN: 235358 Hom.: 13 AF XY: 0.00938 AC XY: 1194 AN XY: 127324

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.00243

Gnomad SAS exome AF: 0.00506

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.00998 AC: 14334 AN: 1435720 Hom.: 88 Cov.: 34 AF XY: 0.00996 AC XY: 7110 AN XY: 713612

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.00771

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0164 AC: 2295 AN: 139844 Hom.: 18 Cov.: 32 AF XY: 0.0167 AC XY: 1143 AN XY: 68330

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00829

Gnomad4 ASJ AF: 0.0180

Gnomad4 EAS AF: 0.00647

Gnomad4 SAS AF: 0.0148

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0233 Hom.: 4

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0122 AC: 1475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital adrenal hyperplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Deficiency of steroid 11-beta-monooxygenase Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.29
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.11
Sift	Benign	0.60	T
Sift4G	Benign	0.69	T
ClinPred		0.0045	T
GERP RS		-5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61752794; hg19: chr8-143956748; COSMIC: COSV52829558;