NM_019885.4:c.1259C>G

Variant names:

• chr2-72132507-G-C
• rs7568553
• NM_019885.4:c.1259C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/21 in silico tools predict 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. A420T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (57 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (44 hom.)
• Consequence: CYP26B1 NM_019885.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.59
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 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.1259C>G	p.Ala420Gly	missense	Exon 6 of 6	NP_063938.1	Q9NR63-1
	CYP26B1	NM_001277742.2		c.1034C>G	p.Ala345Gly	missense	Exon 5 of 5	NP_001264671.1	Q9NR63-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26B1	ENST00000001146.7	TSL:1 MANE Select	c.1259C>G	p.Ala420Gly	missense	Exon 6 of 6	ENSP00000001146.2	Q9NR63-1
	CYP26B1	ENST00000546307.5	TSL:1	c.1034C>G	p.Ala345Gly	missense	Exon 5 of 5	ENSP00000443304.1	Q9NR63-2
	CYP26B1	ENST00000412253.1	TSL:1	c.686C>G	p.Ala229Gly	missense	Exon 5 of 5	ENSP00000401465.1	E7ER08

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2165 AN: 152206 Hom.: 57 Cov.: 33

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

GnomAD2 exomes AF: 0.00409 AC: 1017 AN: 248380 AF XY: 0.00313

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 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.: 44 Cov.: 32 AF XY: 0.00158 AC XY: 1150 AN XY: 726018

African (AFR) AF: 0.0503 AC: 1684 AN: 33458

American (AMR) AF: 0.00383 AC: 171 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52966

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5762

European-Non Finnish (NFE) AF: 0.000443 AC: 492 AN: 1110966

Other (OTH) AF: 0.00386 AC: 233 AN: 60322

GnomAD4 genome AF: 0.0142 AC: 2169 AN: 152324 Hom.: 57 Cov.: 33 AF XY: 0.0142 AC XY: 1058 AN XY: 74488

African (AFR) AF: 0.0476 AC: 1976 AN: 41554

American (AMR) AF: 0.00889 AC: 136 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68032

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00108 Hom.: 2

Bravo AF: 0.0169

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0447 AC: 197

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00479 AC: 582

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	CYP26B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.044
Sift	Benign	0.42	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.037
MVP		0.46
MPC		0.29
ClinPred		0.0075	T
GERP RS		4.2
Varity_R		0.075
gMVP		0.50
Mutation Taster		=94/6	polymorphism

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: rs7568553; hg19: chr2-72359636;