rs2286822

Variant names:

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

Variant summary

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

The NM_001382655.3(POR):​c.1293+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_001382655.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.31
• Publications: 15 publications found

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]

POR Gene-Disease associations (from GenCC):

• Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
• congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382655.3. 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
	POR	NM_001395413.1	MANE Select	c.1239+12C>T		intron	N/A	NP_001382342.1
	POR	NM_001382655.3		c.1293+12C>T		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.1239+12C>T		intron	N/A	NP_001354491.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000461988.6	TSL:1 MANE Select	c.1239+12C>T		intron	N/A	ENSP00000419970.2
	POR	ENST00000447222.5	TSL:5	c.1398+12C>T		intron	N/A	ENSP00000393527.1
	POR	ENST00000910548.1		c.1239+12C>T		intron	N/A	ENSP00000580607.1

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

GnomAD2 exomes AF: 0.312 AC: 69624 AN: 223478 AF XY: 0.307

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 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

African (AFR) AF: 0.220 AC: 7302 AN: 33128

American (AMR) AF: 0.361 AC: 15705 AN: 43480

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 10520 AN: 24288

East Asian (EAS) AF: 0.416 AC: 16192 AN: 38904

South Asian (SAS) AF: 0.249 AC: 20606 AN: 82726

European-Finnish (FIN) AF: 0.232 AC: 10825 AN: 46656

Middle Eastern (MID) AF: 0.363 AC: 2032 AN: 5596

European-Non Finnish (NFE) AF: 0.302 AC: 330358 AN: 1093048

Other (OTH) AF: 0.315 AC: 18525 AN: 58896

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

African (AFR) AF: 0.222 AC: 9200 AN: 41422

American (AMR) AF: 0.308 AC: 4698 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1511 AN: 3446

East Asian (EAS) AF: 0.423 AC: 2159 AN: 5100

South Asian (SAS) AF: 0.242 AC: 1158 AN: 4794

European-Finnish (FIN) AF: 0.237 AC: 2508 AN: 10578

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.302 AC: 20484 AN: 67748

Other (OTH) AF: 0.296 AC: 620 AN: 2096

Alfa AF: 0.287 Hom.: 600

Bravo AF: 0.293

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (2)
-	-	2	not provided (2)
-	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)
-	-	1	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.014
DANN	Benign	0.72
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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