2-72132349-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019885.4(CYP26B1):c.1417C>T(p.Arg473Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,610,680 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R473S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0059 ( 11 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 8 hom. )

Consequence

CYP26B1
NM_019885.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.31

Publications

5 publications found

Variant links:

Genes affected

CYP26B1 (HGNC:20581): (cytochrome P450 family 26 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The encoded protein is localized to the endoplasmic reticulum, and functions as a critical regulator of all-trans retinoic acid levels by the specific inactivation of all-trans retinoic acid to hydroxylated forms. Mutations in this gene are associated with radiohumeral fusions and other skeletal and craniofacial anomalies, and increased levels of the encoded protein are associated with atherosclerotic lesions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2013]

CYP26B1 Gene-Disease associations (from GenCC):

lethal occipital encephalocele-skeletal dysplasia syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

CYP26B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.008088917).

BP6

Variant 2-72132349-G-A is Benign according to our data. Variant chr2-72132349-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 790505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00591 (900/152278) while in subpopulation AFR AF = 0.0208 (865/41562). AF 95% confidence interval is 0.0197. There are 11 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019885.4. 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
	CYP26B1	NM_019885.4	MANE Select	c.1417C>T	p.Arg473Cys	missense	Exon 6 of 6	NP_063938.1	Q9NR63-1
	CYP26B1	NM_001277742.2		c.1192C>T	p.Arg398Cys	missense	Exon 5 of 5	NP_001264671.1	Q9NR63-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP26B1	ENST00000001146.7	TSL:1 MANE Select	c.1417C>T	p.Arg473Cys	missense	Exon 6 of 6	ENSP00000001146.2	Q9NR63-1
CYP26B1	ENST00000546307.5	TSL:1	c.1192C>T	p.Arg398Cys	missense	Exon 5 of 5	ENSP00000443304.1	Q9NR63-2
CYP26B1	ENST00000412253.1	TSL:1	c.844C>T	p.Arg282Cys	missense	Exon 5 of 5	ENSP00000401465.1	E7ER08

Frequencies

GnomAD3 genomes

AF:

0.00589

AC:

896

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00153

AC:

375

AN:

245756

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.0214

Gnomad AMR exome

AF:

0.000851

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000631

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000614

AC:

895

AN:

1458402

Hom.:

Cov.:

AF XY:

0.000530

AC XY:

384

AN XY:

725004

show subpopulations

African (AFR)

AF:

0.0225

AC:

752

AN:

33420

American (AMR)

AF:

0.000856

AC:

AN:

44412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39566

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53148

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1109914

Other (OTH)

AF:

0.00110

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00591

AC:

900

AN:

152278

Hom.:

Cov.:

AF XY:

0.00564

AC XY:

420

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0208

AC:

865

AN:

41562

American (AMR)

AF:

0.00111

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68016

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00196

Hom.:

Bravo

AF:

0.00672

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00192

AC:

233

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.8

PhyloP100

5.3

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Uncertain

0.022

Sift4G

Uncertain

0.032

Polyphen

0.92

Vest4

0.48

MVP

0.65

MPC

1.0

ClinPred

0.052

GERP RS

5.6

Varity_R

0.17

gMVP

0.84

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over