rs267601810

chr8-142877196-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000497.4(CYP11B1):c.422G>A(p.Arg141Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,836 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 5.54

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 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000497.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 8-142877196-C-T is Pathogenic according to our data. Variant chr8-142877196-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 77208.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.422G>A	p.Arg141Gln	missense_variant	3/9	ENST00000292427.10
CYP11B1	NM_001026213.1	c.422G>A	p.Arg141Gln	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.422G>A	p.Arg141Gln	missense_variant	3/9	1	NM_000497.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250542 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135432

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: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461644 Hom.: 0 Cov.: 40 AF XY: 0.00000688 AC XY: 5 AN XY: 727082

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 04, 2018	- -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the CYP11B1 protein (p.Arg141Gln). This variant is present in population databases (rs267601810, gnomAD 0.003%). This missense change has been observed in individuals with 11-beta-hydroxylase deficiency (PMID: 24987415, 26956189). ClinVar contains an entry for this variant (Variation ID: 77208). 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 with a positive predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2018	- -

CYP11B1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

The CYP11B1 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141Gln. This variant has been reported in a compound heterozygous state with another variant in individuals with 11 beta-hydroxylase deficiency (Dumic et al. 2014. PubMed ID: 24987415; Table S1 - Khattab et al. 2017. PubMed ID: 28228528). This variant was also reported with another novel variant in an individual with 11 beta-hydroxylase deficiency (Kandemir et al. 2017. PubMed ID: 26956189). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143958612-C-T). This variant falls within a highly paralogous region. Allele frequency data should be interpreted with caution. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	0.59	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.68
MutPred		0.88		.;.;Loss of MoRF binding (P = 0.0663);
MVP		0.95
MPC		0.47
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.97
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267601810; hg19: chr8-143958612; COSMIC: COSV99454509; COSMIC: COSV99454509;