rs2241057

Positions:

• chr2-72134831-A-G

Variant summary

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

The ENST00000001146.7(CYP26B1):​c.791T>C​(p.Leu264Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,614,020 control chromosomes in the GnomAD database, including 23,829 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3216 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20613 hom.)
• Consequence: CYP26B1 ENST00000001146.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004927933).
• BP6: Variant 2-72134831-A-G is Benign according to our data. Variant chr2-72134831-A-G is described in ClinVar as [Benign]. Clinvar id is 1180923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP26B1	NM_019885.4	c.791T>C	p.Leu264Ser	missense_variant	4/6	ENST00000001146.7	NP_063938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP26B1	ENST00000001146.7	c.791T>C	p.Leu264Ser	missense_variant	4/6	1	NM_019885.4	ENSP00000001146	P1
CYP26B1	ENST00000546307.5	c.566T>C	p.Leu189Ser	missense_variant	3/5	1		ENSP00000443304
CYP26B1	ENST00000412253.1	c.218T>C	p.Leu73Ser	missense_variant	3/5	1		ENSP00000401465
CYP26B1	ENST00000474509.1			downstream_gene_variant		4		ENSP00000430888

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29139 AN: 152054 Hom.: 3187 Cov.: 33

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0738

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.169 AC: 42396 AN: 251358 Hom.: 4391 AF XY: 0.159 AC XY: 21667 AN XY: 135852

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.0676

Gnomad SAS exome AF: 0.0910

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.162 AC: 236273 AN: 1461848 Hom.: 20613 Cov.: 35 AF XY: 0.158 AC XY: 114852 AN XY: 727226

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.0773

Gnomad4 SAS exome AF: 0.0928

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.192 AC: 29213 AN: 152172 Hom.: 3216 Cov.: 33 AF XY: 0.189 AC XY: 14029 AN XY: 74396

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.0737

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.189

Alfa AF: 0.161 Hom.: 5676

Bravo AF: 0.206

TwinsUK AF: 0.168 AC: 623

ALSPAC AF: 0.162 AC: 624

ESP6500AA AF: 0.282 AC: 1242

ESP6500EA AF: 0.154 AC: 1321

ExAC AF: 0.165 AC: 20000

Asia WGS AF: 0.130 AC: 452 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.162

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	This variant is associated with the following publications: (PMID: 22415012) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.041	.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.0070	T;T;T
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	.;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.8	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.86	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.033
MPC		0.39
ClinPred		0.0030	T
GERP RS		3.3
Varity_R		0.034
gMVP		0.17

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: rs2241057; hg19: chr2-72361960; COSMIC: COSV50011863; COSMIC: COSV50011863;