rs2286965

Positions:

• chr2-72133031-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000001146.7(CYP26B1):​c.1138G>A​(p.Glu380Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000929 in 1,613,204 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts 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 0.00084 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (29 hom.)
• Consequence: CYP26B1 ENST00000001146.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.15

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014027476).
• BP6: Variant 2-72133031-C-T is Benign according to our data. Variant chr2-72133031-C-T is described in ClinVar as [Benign]. Clinvar id is 715945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00084 (128/152352) while in subpopulation EAS AF= 0.0185 (96/5182). AF 95% confidence interval is 0.0155. There are 3 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP26B1	NM_019885.4	c.1138G>A	p.Glu380Lys	missense_variant	5/6	ENST00000001146.7	NP_063938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP26B1	ENST00000001146.7	c.1138G>A	p.Glu380Lys	missense_variant	5/6	1	NM_019885.4	ENSP00000001146	P1
CYP26B1	ENST00000546307.5	c.913G>A	p.Glu305Lys	missense_variant	4/5	1		ENSP00000443304
CYP26B1	ENST00000412253.1	c.565G>A	p.Glu189Lys	missense_variant	4/5	1		ENSP00000401465

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00202 AC: 499 AN: 247586 Hom.: 10 AF XY: 0.00172 AC XY: 232 AN XY: 134520

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000997

Gnomad EAS exome AF: 0.0254

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000453

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000938 AC: 1371 AN: 1460852 Hom.: 29 Cov.: 33 AF XY: 0.000893 AC XY: 649 AN XY: 726748

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0308

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74504

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00128 Hom.: 6

Bravo AF: 0.000774

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.8	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.078	T;T;T
Polyphen		0.99	.;D;.
Vest4		0.87
MVP		0.91
MPC		1.0
ClinPred		0.070	T
GERP RS		5.1
Varity_R		0.61
gMVP		0.71

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: rs2286965; hg19: chr2-72360160; COSMIC: COSV99134269; COSMIC: COSV99134269;