2-72134831-A-G

Variant names:

• chr2-72134831-A-G
• rs2241057
• NM_019885.4:c.791T>C

Variant summary

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

The NM_019885.4(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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3216 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20613 hom.)
• Consequence: CYP26B1 NM_019885.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.56
• Publications: 63 publications found

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, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26B1	NM_019885.4	MANE Select	c.791T>C	p.Leu264Ser	missense	Exon 4 of 6	NP_063938.1
	CYP26B1	NM_001277742.2		c.566T>C	p.Leu189Ser	missense	Exon 3 of 5	NP_001264671.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26B1	ENST00000001146.7	TSL:1 MANE Select	c.791T>C	p.Leu264Ser	missense	Exon 4 of 6	ENSP00000001146.2
	CYP26B1	ENST00000546307.5	TSL:1	c.566T>C	p.Leu189Ser	missense	Exon 3 of 5	ENSP00000443304.1
	CYP26B1	ENST00000412253.1	TSL:1	c.218T>C	p.Leu73Ser	missense	Exon 3 of 5	ENSP00000401465.1

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

GnomAD2 exomes AF: 0.169 AC: 42396 AN: 251358 AF XY: 0.159

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 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

African (AFR) AF: 0.291 AC: 9728 AN: 33478

American (AMR) AF: 0.303 AC: 13567 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3354 AN: 26134

East Asian (EAS) AF: 0.0773 AC: 3070 AN: 39700

South Asian (SAS) AF: 0.0928 AC: 8007 AN: 86258

European-Finnish (FIN) AF: 0.141 AC: 7521 AN: 53404

Middle Eastern (MID) AF: 0.120 AC: 692 AN: 5768

European-Non Finnish (NFE) AF: 0.162 AC: 180479 AN: 1111996

Other (OTH) AF: 0.163 AC: 9855 AN: 60394

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

African (AFR) AF: 0.290 AC: 12046 AN: 41492

American (AMR) AF: 0.219 AC: 3345 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 453 AN: 3472

East Asian (EAS) AF: 0.0737 AC: 382 AN: 5180

South Asian (SAS) AF: 0.0909 AC: 439 AN: 4828

European-Finnish (FIN) AF: 0.142 AC: 1512 AN: 10614

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10537 AN: 67986

Other (OTH) AF: 0.189 AC: 400 AN: 2112

Alfa AF: 0.166 Hom.: 11635

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22415012)

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.058
Sift	Benign	0.86	T
Sift4G	Benign	1.0	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
Mutation Taster		=97/3	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: rs2241057; hg19: chr2-72361960; COSMIC: COSV50011863; COSMIC: COSV50011863;