8-142875713-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000497.4(CYP11B1):c.1120C>A(p.Arg374=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,594,996 control chromosomes in the GnomAD database, including 413 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (24 hom., cov: 31)
  • Exomes 𝑓: 0.022 (389 hom.)
• Consequence: CYP11B1 NM_000497.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006423
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.175

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-142875713-G-T is Benign according to our data. Variant chr8-142875713-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 35981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142875713-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.175 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0217 (2929/135086) while in subpopulation SAS AF= 0.0295 (119/4036). AF 95% confidence interval is 0.0277. There are 24 homozygotes in gnomad4. There are 1321 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.1120C>A	p.Arg374=	splice_region_variant, synonymous_variant	6/9	ENST00000292427.10
CYP11B1	NM_001026213.1	c.1120C>A	p.Arg374=	splice_region_variant, synonymous_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1120C>A	p.Arg374=	splice_region_variant, synonymous_variant	6/9	1	NM_000497.4	P1

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 2926 AN: 135006 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00676

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0203

GnomAD3 exomes AF: 0.0174 AC: 4327 AN: 248518 Hom.: 57 AF XY: 0.0183 AC XY: 2470 AN XY: 134656

Gnomad AFR exome AF: 0.00374

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0220 AC: 32135 AN: 1459910 Hom.: 389 Cov.: 33 AF XY: 0.0219 AC XY: 15915 AN XY: 726290

Gnomad4 AFR exome AF: 0.00390

Gnomad4 AMR exome AF: 0.00717

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.000305

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0180

GnomAD4 genome AF: 0.0217 AC: 2929 AN: 135086 Hom.: 24 Cov.: 31 AF XY: 0.0201 AC XY: 1321 AN XY: 65738

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.0295

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0288

Gnomad4 OTH AF: 0.0201

Alfa AF: 0.0189 Hom.: 12

EpiCase AF: 0.0234

EpiControl AF: 0.0236

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CYP11B1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2019	Variant summary: CYP11B1 c.1120C>A (p.Arg374Arg) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another tool for predicting the outcome of synonymous variants, namely Transcript-inferred Pathogenicity score (TraP, Gelfman_2017) predicts this variant to be possibly pathogenic. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.017 in 248518 control chromosomes in the gnomAD database, including 57 homozygotes. The observed variant frequency is approximately 8.5 fold the estimated maximal allele frequency expected for a pathogenic variant in CYP11B1 causing Congenital Adrenal Hyperplasia phenotype (0.002), strongly suggesting that the variant is benign. c.1120C>A has been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia, but without strong evidence for causality (Dundar_2019). This report does not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (too high for associated disease - congenital adrenal hyperplasia) -

Deficiency of steroid 11-beta-monooxygenase Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Apr 20, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Glucocorticoid-remediable aldosteronism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	5.2
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.054
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: rs61752786; hg19: chr8-143957129; COSMIC: COSV52830598;