rs2286822

Variant names:

• chr7-75984970-C-T
• rs2286822
• NM_001395413.1:c.1239+12C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.1239+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,578,350 control chromosomes in the GnomAD database, including 73,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6219 hom., cov: 32)
  • Exomes 𝑓: 0.30 (67091 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.31

Genes affected

POR (HGNC:9208): (cytochrome p450 oxidoreductase) This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-75984970-C-T is Benign according to our data. Variant chr7-75984970-C-T is described in ClinVar as [Benign]. Clinvar id is 256838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75984970-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POR	NM_001395413.1	c.1239+12C>T		intron_variant	Intron 11 of 15	ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.1239+12C>T		intron_variant	Intron 11 of 15	1	NM_001395413.1	ENSP00000419970.2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42649 AN: 151510 Hom.: 6210 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.312 AC: 69624 AN: 223478 Hom.: 11147 AF XY: 0.307 AC XY: 37437 AN XY: 121846

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.305

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.303 AC: 432065 AN: 1426722 Hom.: 67091 Cov.: 44 AF XY: 0.302 AC XY: 213041 AN XY: 705662

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.416

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.282 AC: 42687 AN: 151628 Hom.: 6219 Cov.: 32 AF XY: 0.278 AC XY: 20587 AN XY: 74128

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.296

Alfa AF: 0.287 Hom.: 600

Bravo AF: 0.293

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1

-

Pecori Giraldi Lab, University of Milan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: case-control

This variant is intronic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.014
DANN	Benign	0.72

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: rs2286822; hg19: chr7-75614288; COSMIC: COSV58694257; COSMIC: COSV58694257;