8-142879690-G-C

Position:

• chr8-142879690-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000292427.10(CYP11B1):​c.124C>G​(p.Pro42Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP11B1 ENST00000292427.10 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.61

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-142879689-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 8-142879690-G-C is Pathogenic according to our data. Variant chr8-142879690-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1347207.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.124C>G	p.Pro42Ala	missense_variant	1/9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.124C>G	p.Pro42Ala	missense_variant	1/8		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.124C>G	p.Pro42Ala	missense_variant	1/9	1	NM_000497.4	ENSP00000292427	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro42 amino acid residue in CYP11B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9302260, 26053152, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP11B1 protein function. This variant has not been reported in the literature in individuals with CYP11B1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 42 of the CYP11B1 protein (p.Pro42Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.29
MutPred		0.80		Loss of glycosylation at P42 (P = 0.0107);Loss of glycosylation at P42 (P = 0.0107);Loss of glycosylation at P42 (P = 0.0107);
MVP		0.96
MPC		0.46
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.62
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-143961106;