2-72132507-G-C

Position:

chr2-72132507-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019885.4(CYP26B1):c.1259C>G(p.Ala420Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,612,324 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.014 ( 57 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 44 hom. )

Consequence

CYP26B1
NM_019885.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.59

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022057593).

BP6

Variant 2-72132507-G-C is Benign according to our data. Variant chr2-72132507-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 445321.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 = 0.0142 (2169/152324) while in subpopulation AFR AF= 0.0476 (1976/41554). AF 95% confidence interval is 0.0458. There are 57 homozygotes in gnomad4. There are 1058 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP26B1	NM_019885.4 linkuse as main transcript	c.1259C>G	p.Ala420Gly	missense_variant	6/6	ENST00000001146.7	NP_063938.1	Q9NR63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CYP26B1	ENST00000001146.7 linkuse as main transcript	c.1259C>G	p.Ala420Gly	missense_variant	6/6	1	NM_019885.4	ENSP00000001146.2	Q9NR63-1
CYP26B1	ENST00000546307.5 linkuse as main transcript	c.1034C>G	p.Ala345Gly	missense_variant	5/5	1		ENSP00000443304.1	Q9NR63-2
CYP26B1	ENST00000412253.1 linkuse as main transcript	c.686C>G	p.Ala229Gly	missense_variant	5/5	1		ENSP00000401465.1	E7ER08

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2165

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00409

AC:

1017

AN:

248380

Hom.:

AF XY:

0.00313

AC XY:

421

AN XY:

134524

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.00339

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000594

Gnomad OTH exome

AF:

0.00312

GnomAD4 exome

AF:

0.00181

AC:

2640

AN:

1460000

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1150

AN XY:

726018

show subpopulations

Gnomad4 AFR exome

AF:

0.0503

Gnomad4 AMR exome

AF:

0.00383

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000443

Gnomad4 OTH exome

AF:

0.00386

GnomAD4 genome

AF:

0.0142

AC:

2169

AN:

152324

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1058

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0476

Gnomad4 AMR

AF:

0.00889

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.0169

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0447

AC:

197

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00479

AC:

582

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CYP26B1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

.;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.80

N;N;N

REVEL

Benign

0.044

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.037

MVP

0.46

MPC

0.29

ClinPred

0.0075

GERP RS

4.2

Varity_R

0.075

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over