rs1040312

Variant names:

• chr6-32039531-C-A
• rs1040312
• NM_000500.9:c.550-15C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32039531-C-A
• chr6-32039531-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000500.9(CYP21A2):​c.550-15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,550,408 control chromosomes in the GnomAD database, including 1,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (196 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1045 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.477
• Publications: 6 publications found

Genes affected

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) 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 and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP21A2 Gene-Disease associations (from GenCC):

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-32039531-C-A is Benign according to our data. Variant chr6-32039531-C-A is described in ClinVar as Benign. ClinVar VariationId is 256294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 196 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.550-15C>A		intron_variant	Intron 4 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.460-15C>A		intron_variant	Intron 3 of 8		NP_001122062.3
CYP21A2	NM_001368143.2	c.145-15C>A		intron_variant	Intron 4 of 9		NP_001355072.1
CYP21A2	NM_001368144.2	c.145-15C>A		intron_variant	Intron 3 of 8		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.550-15C>A		intron_variant	Intron 4 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6330 AN: 147382 Hom.: 197 Cov.: 31

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.0661

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.00783

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0380

GnomAD2 exomes AF: 0.0129 AC: 2652 AN: 205752 AF XY: 0.0118

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0335

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00761

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0136 AC: 19089 AN: 1402910 Hom.: 1045 Cov.: 61 AF XY: 0.0138 AC XY: 9599 AN XY: 695690

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0409 AC: 1315 AN: 32178

American (AMR) AF: 0.0201 AC: 780 AN: 38812

Ashkenazi Jewish (ASJ) AF: 0.00626 AC: 160 AN: 25568

East Asian (EAS) AF: 0.0176 AC: 667 AN: 37908

South Asian (SAS) AF: 0.0185 AC: 1512 AN: 81928

European-Finnish (FIN) AF: 0.0776 AC: 3858 AN: 49746

Middle Eastern (MID) AF: 0.00877 AC: 50 AN: 5702

European-Non Finnish (NFE) AF: 0.00906 AC: 9720 AN: 1072708

Other (OTH) AF: 0.0176 AC: 1027 AN: 58360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0430 AC: 6340 AN: 147498 Hom.: 196 Cov.: 31 AF XY: 0.0449 AC XY: 3224 AN XY: 71834

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0584 AC: 2358 AN: 40358

American (AMR) AF: 0.0361 AC: 526 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.00783 AC: 27 AN: 3448

East Asian (EAS) AF: 0.0371 AC: 186 AN: 5012

South Asian (SAS) AF: 0.0228 AC: 107 AN: 4702

European-Finnish (FIN) AF: 0.107 AC: 1033 AN: 9654

Middle Eastern (MID) AF: 0.0517 AC: 15 AN: 290

European-Non Finnish (NFE) AF: 0.0294 AC: 1953 AN: 66526

Other (OTH) AF: 0.0376 AC: 77 AN: 2046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0319 Hom.: 23

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYP21A2 c.550-15C>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. The variant allele was found at a frequency of 0.013 in 205752 control chromosomes in the gnomAD database, including 191 homozygotes. The observed variant frequency is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP21A2 causing Congenital Adrenal Hyperplasia phenotype (0.002). To our knowledge, no occurrence of c.550-15C>A in individuals affected with Congenital Adrenal Hyperplasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 256294). Based on the evidence outlined above, the variant was classified as benign. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.75
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs1040312; hg19: chr6-32007308; COSMIC: COSV64482179; COSMIC: COSV64482179;