rs61754263

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_000102.4(CYP17A1):c.62G>A(p.Arg21Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,610,768 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

CYP17A1
NM_000102.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:1

Conservation

PhyloP100: -0.656

Publications

5 publications found

Variant links:

Genes affected

CYP17A1 (HGNC:2593): (cytochrome P450 family 17 subfamily A 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 protein localizes to the endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. Mutations in this gene are associated with isolated steroid-17 alpha-hydroxylase deficiency, 17-alpha-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia. [provided by RefSeq, Jul 2008]

CYP17A1 Gene-Disease associations (from GenCC):

congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
46,XY disorder of sex development due to isolated 17,20-lyase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP17A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2356 (below the threshold of 3.09). Trascript score misZ: 1.3377 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, 46,XY disorder of sex development due to isolated 17,20-lyase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.01217252).

BP6

Variant 10-102837300-C-T is Benign according to our data. Variant chr10-102837300-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298626.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00114 (173/152312) while in subpopulation AMR AF = 0.00196 (30/15296). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000102.4. 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
	CYP17A1	NM_000102.4	MANE Select	c.62G>A	p.Arg21Lys	missense	Exon 1 of 8	NP_000093.1	Q1HB44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP17A1	ENST00000369887.4	TSL:1 MANE Select	c.62G>A	p.Arg21Lys	missense	Exon 1 of 8	ENSP00000358903.3	P05093
CYP17A1	ENST00000960108.1		c.62G>A	p.Arg21Lys	missense	Exon 1 of 8	ENSP00000630166.1
CYP17A1	ENST00000960123.1		c.62G>A	p.Arg21Lys	missense	Exon 1 of 8	ENSP00000630182.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000791

AC:

199

AN:

251424

AF XY:

0.000780

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00123

AC:

1794

AN:

1458456

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

849

AN XY:

725856

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33406

American (AMR)

AF:

0.000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00152

AC:

1684

AN:

1108914

Other (OTH)

AF:

0.000780

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

167

250

334

417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152312

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41584

American (AMR)

AF:

0.00196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00178

AC:

121

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.000876

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000898

AC:

109

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of steroid 17-alpha-monooxygenase (3)

not provided (2)

Congenital adrenal hyperplasia (1)

CYP17A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.60

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.31

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.66

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.24

PhyloP100

-0.66

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.10

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.64

MVP

0.61

MPC

0.28

ClinPred

0.0032

GERP RS

-3.8

PromoterAI

-0.0038

Neutral

(source)

Varity_R

0.038

gMVP

0.21

Mutation Taster

=42/58

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over