chr10-93061436-T-C

Variant names:

• chr10-93061436-T-C
• rs766542384
• NM_183374.3:c.173T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_183374.3(CYP26C1):​c.173T>C​(p.Phe58Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F58Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CYP26C1 NM_183374.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

Genes affected

CYP26C1 (HGNC:20577): (cytochrome P450 family 26 subfamily C member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is involved in the catabolism of all-trans- and 9-cis-retinoic acid, and thus contributes to the regulation of retinoic acid levels in cells and tissues. This gene is adjacent to a related gene on chromosome 10q23.33. [provided by RefSeq, Jul 2008]

CYP26C1-DT (HGNC:55836): (CYP26C1 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183374.3. 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
	CYP26C1	NM_183374.3	MANE Select	c.173T>C	p.Phe58Ser	missense	Exon 1 of 6	NP_899230.2	Q6V0L0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26C1	ENST00000651965.1	MANE Select	c.173T>C	p.Phe58Ser	missense	Exon 1 of 6	ENSP00000498424.1	Q6V0L0
	CYP26C1	ENST00000624358.3	TSL:2	n.173T>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000485098.1	A0A096LNL5
	CYP26C1-DT	ENST00000847325.1		n.532+631A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402070 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 691988

African (AFR) AF: 0.00 AC: 0 AN: 31922

American (AMR) AF: 0.00 AC: 0 AN: 36186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 36226

South Asian (SAS) AF: 0.00 AC: 0 AN: 79528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5082

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081378

Other (OTH) AF: 0.00 AC: 0 AN: 58122

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.88		Gain of disorder (P = 0.0084)
MVP		0.94
MPC		2.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
Mutation Taster		=65/35	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: rs766542384; hg19: chr10-94821193;