rs61754263

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_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. 16/21 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:4B:1O:1

Conservation

PhyloP100: -0.656

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 298626.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, not_provided=1}. Variant chr10-102837300-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP17A1	NM_000102.4 link	c.62G>A	p.Arg21Lys	missense_variant	Exon 1 of 8	ENST00000369887.4	NP_000093.1	P05093Q1HB44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP17A1	ENST00000369887.4 link	c.62G>A	p.Arg21Lys	missense_variant	Exon 1 of 8	1	NM_000102.4	ENSP00000358903.3		P05093

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

GnomAD3 exomes

AF:

0.000791

AC:

199

AN:

251424

Hom.:

AF XY:

0.000780

AC XY:

106

AN XY:

135884

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 SAS 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

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.00152

Gnomad4 OTH exome

AF:

0.000780

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152312

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00160

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 34426522, Rokhaya _ 2020_article, 19636199) -

Deficiency of steroid 17-alpha-monooxygenase

Uncertain:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CYP17A1-related disorder

Uncertain:1

Jul 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CYP17A1 c.62G>A variant is predicted to result in the amino acid substitution p.Arg21Lys. This variant has been reported in the homozygous state in an individual with congenital adrenal hyperplasia (CAH) due to 17-alpha-hydroxylase/17,20-lyase deficiency (Nuzzo et al. 2009. PubMed ID: 19636199). This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD. The p.Arg21 residue is weakly conserved and at this position is a lysine (Lys) in many species including rat, mouse and dog. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Congenital adrenal hyperplasia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62G>A (p.Arg21Lys) variant was reported in a homozygous state in a patient with congenital adrenal hyperplasia due to 17alpha-hydroxylase/17,20-lyase deficiency (Nuzzo et al. 2009). Studies of available family members showed that the patient's unaffected mother and sister were both heterozygous for this variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00298 in the European population of the 1000 Genomes Project. The evidence for this variant is limited. The p.Arg21Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for congenital adrenal hyperplasia. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.60

DANN

Benign

0.65

DEOGEN2

Benign

0.31

.;.;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.66

T;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.24

.;.;N;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.10

.;.;N;.;.

REVEL

Benign

0.23

Sift

Benign

1.0

.;.;T;.;.

Sift4G

Benign

1.0

.;.;T;.;.

Polyphen

0.0010

.;.;B;.;.

Vest4

0.64

MVP

0.61

MPC

0.28

ClinPred

0.0032

GERP RS

-3.8

Varity_R

0.038

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over