rs775128501

chr8-142876353-C-CTGGTGTACTGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000497.4(CYP11B1):c.841_842insACAGTACACCA(p.Ser281AsnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.908

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-142876353-C-CTGGTGTACTGT is Pathogenic according to our data. Variant chr8-142876353-C-CTGGTGTACTGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.841_842insACAGTACACCA	p.Ser281AsnfsTer19	frameshift_variant	5/9	ENST00000292427.10
CYP11B1	NM_001026213.1	c.841_842insACAGTACACCA	p.Ser281AsnfsTer19	frameshift_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.841_842insACAGTACACCA	p.Ser281AsnfsTer19	frameshift_variant	5/9	1	NM_000497.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251254 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461828 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2023	This sequence change creates a premature translational stop signal (p.Ser281Asnfs*19) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331). This variant is present in population databases (rs775128501, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 24334966). This variant is also known as 3467^3468insACAGTACACCA. ClinVar contains an entry for this variant (Variation ID: 447227). For these reasons, this variant has been classified as Pathogenic. -

Deficiency of steroid 11-beta-monooxygenase Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775128501; hg19: chr8-143957769;