rs1412048304

Positions:

• chr8-142875289-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_000497.4(CYP11B1):​c.1145T>G​(p.Leu382Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.29

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 Uncertain_significance. Variant got 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 8-142875289-A-C is Pathogenic according to our data. Variant chr8-142875289-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557468.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.1145T>G	p.Leu382Arg	missense_variant	7/9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.1145T>G	p.Leu382Arg	missense_variant	7/8		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1145T>G	p.Leu382Arg	missense_variant	7/9	1	NM_000497.4	ENSP00000292427.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250738 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461296 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 726944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 27, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2023	- -

Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 20, 2024

- -

Congenital adrenal hyperplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 20, 2024

Variant summary: CYP11B1 c.1145T>G (p.Leu382Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250738 control chromosomes. c.1145T>G has been reported in the literature in the compound heterozygous state in a female individual with a diagnosis of classic 11-beta-hydroxylase deficiency (Mooij_2015). This suggests the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in a complete loss of CYP11B1 enzymatic activity in vitro (Mooij_2015). The following publication has been ascertained in the context of this evaluation (PMID: 26053152). ClinVar contains an entry for this variant (Variation ID: 557468). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;D;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Uncertain	2.8	.;M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.11	T;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.95, 0.93	.;P;.;P
Vest4		0.59, 0.57, 0.58
MutPred		0.87		.;.;.;Gain of catalytic residue at L453 (P = 0.0317);
MVP		0.90
MPC		0.53
ClinPred		0.74	D
GERP RS		3.1
Varity_R		0.79
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1412048304; hg19: chr8-143956705;