rs104894071

Positions:

• chr8-142875730-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000497.4(CYP11B1):​c.1103C>A​(p.Ala368Asp) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.42

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]

CYP11B1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 8-142875730-G-T is Pathogenic according to our data. Variant chr8-142875730-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1187.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.1103C>A	p.Ala368Asp	missense_variant	6/9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.1103C>A	p.Ala368Asp	missense_variant	6/8		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1103C>A	p.Ala368Asp	missense_variant	6/9	1	NM_000497.4	ENSP00000292427.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	.;M;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D
Vest4		0.77, 0.83, 0.91
MutPred		0.83		.;.;.;Loss of ubiquitination at K441 (P = 0.0661);
MVP		0.95
MPC		0.57
ClinPred		1.0	D
GERP RS		4.4
Varity_R		1.0
gMVP		0.96

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: rs104894071; hg19: chr8-143957146;