chr8-142874500-C-G

Variant names:

• chr8-142874500-C-G
• rs5295
• NM_000497.4:c.1399-14G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000497.4(CYP11B1):​c.1399-14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 1,587,936 control chromosomes in the GnomAD database, including 7,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1575 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5943 hom.)
• Consequence: CYP11B1 NM_000497.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.56
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-142874500-C-G is Benign according to our data. Variant chr8-142874500-C-G is described in ClinVar as Benign. ClinVar VariationId is 362146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000497.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	NM_000497.4	MANE Select	c.1399-14G>C		intron	N/A	NP_000488.3
	CYP11B1	NM_001026213.1		c.1201-14G>C		intron	N/A	NP_001021384.1	P15538-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.1399-14G>C		intron	N/A	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1612-14G>C		intron	N/A	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.1201-14G>C		intron	N/A	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18555 AN: 151956 Hom.: 1569 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.0735

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.0844 AC: 21172 AN: 250882 AF XY: 0.0842

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0489

Gnomad ASJ exome AF: 0.0581

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0718

Gnomad NFE exome AF: 0.0879

Gnomad OTH exome AF: 0.0819

GnomAD4 exome AF: 0.0837 AC: 120201 AN: 1435862 Hom.: 5943 Cov.: 26 AF XY: 0.0841 AC XY: 60236 AN XY: 715964

African (AFR) AF: 0.247 AC: 8130 AN: 32974

American (AMR) AF: 0.0525 AC: 2347 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0601 AC: 1562 AN: 25970

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39558

South Asian (SAS) AF: 0.101 AC: 8620 AN: 85700

European-Finnish (FIN) AF: 0.0688 AC: 3672 AN: 53402

Middle Eastern (MID) AF: 0.151 AC: 864 AN: 5722

European-Non Finnish (NFE) AF: 0.0828 AC: 90143 AN: 1088342

Other (OTH) AF: 0.0816 AC: 4858 AN: 59514

GnomAD4 genome AF: 0.122 AC: 18582 AN: 152074 Hom.: 1575 Cov.: 32 AF XY: 0.119 AC XY: 8859 AN XY: 74346

African (AFR) AF: 0.239 AC: 9888 AN: 41414

American (AMR) AF: 0.0704 AC: 1077 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5172

South Asian (SAS) AF: 0.0932 AC: 449 AN: 4820

European-Finnish (FIN) AF: 0.0735 AC: 780 AN: 10616

Middle Eastern (MID) AF: 0.200 AC: 58 AN: 290

European-Non Finnish (NFE) AF: 0.0854 AC: 5803 AN: 67978

Other (OTH) AF: 0.110 AC: 233 AN: 2112

Alfa AF: 0.0624 Hom.: 89

Bravo AF: 0.126

Asia WGS AF: 0.0480 AC: 170 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of steroid 11-beta-monooxygenase (2)
-	-	2	not provided (2)
-	-	1	Glucocorticoid-remediable aldosteronism (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.17
DANN	Benign	0.61
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5295; hg19: chr8-143955916; COSMIC: COSV52827254;