chr10-102837300-C-T

Variant names:

• chr10-102837300-C-T
• rs61754263
• NM_000102.4:c.62G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

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. 17/23 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: -0.656

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 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 46,XY disorder of sex development due to isolated 17,20-lyase deficiency, congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01217252).
• 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 FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152194 Hom.: 0 Cov.: 32

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

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.: 1 Cov.: 30 AF XY: 0.00117 AC XY: 849 AN XY: 725856

Gnomad4 AFR exome AF: 0.000150 AC: 5 AN: 33406

Gnomad4 AMR exome AF: 0.000447 AC: 20 AN: 44720

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26122

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39674

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86182

Gnomad4 FIN exome AF: 0.000693 AC: 37 AN: 53414

Gnomad4 NFE exome AF: 0.00152 AC: 1684 AN: 1108914

Gnomad4 Remaining exome AF: 0.000780 AC: 47 AN: 60264

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74482

Gnomad4 AFR AF: 0.000216 AC: 0.000216429 AN: 0.000216429

Gnomad4 AMR AF: 0.00196 AC: 0.0019613 AN: 0.0019613

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000941 AC: 0.000941265 AN: 0.000941265

Gnomad4 NFE AF: 0.00178 AC: 0.00177873 AN: 0.00177873

Gnomad4 OTH AF: 0.00142 AC: 0.0014218 AN: 0.0014218

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.000876

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of steroid 17-alpha-monooxygenase Uncertain:2 Other: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

- -

Feb 04, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1 Benign: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) -

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	T
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	N
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.24	.;.;N;.;.
PrimateAI	Benign	0.31	T
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	T
GERP RS		-3.8
Varity_R		0.038
gMVP		0.21
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs61754263; hg19: chr10-104597057;