rs1040311

Variant names:

• chr6-32039538-T-C
• rs1040311
• NM_000500.9:c.550-8T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-32039538-T-C
• chr6-32039538-T-G

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.550-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,541,382 control chromosomes in the GnomAD database, including 1,519 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (160 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1359 hom.)
• Consequence: CYP21A2 NM_000500.9 splice_region, intron
• Scores: Splicing: ADA: 0.00006899
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.602
• Publications: 3 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=-0.91).
• BP6: Variant 6-32039538-T-C is Benign according to our data. Variant chr6-32039538-T-C is described in ClinVar as Benign. ClinVar VariationId is 256295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 160 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.550-8T>C		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.460-8T>C		splice_region_variant, intron_variant	Intron 3 of 8		NP_001122062.3
CYP21A2	NM_001368143.2	c.145-8T>C		splice_region_variant, intron_variant	Intron 4 of 9		NP_001355072.1
CYP21A2	NM_001368144.2	c.145-8T>C		splice_region_variant, 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.550-8T>C		splice_region_variant, intron_variant	Intron 4 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5672 AN: 147230 Hom.: 161 Cov.: 31

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0674

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.00870

Gnomad EAS AF: 0.0338

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0337

GnomAD2 exomes AF: 0.0117 AC: 2426 AN: 206788 AF XY: 0.0110

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0301

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00825

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0144 AC: 20021 AN: 1394040 Hom.: 1359 Cov.: 57 AF XY: 0.0147 AC XY: 10150 AN XY: 691804

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

African (AFR) AF: 0.0194 AC: 621 AN: 31994

American (AMR) AF: 0.0195 AC: 758 AN: 38966

Ashkenazi Jewish (ASJ) AF: 0.00646 AC: 165 AN: 25554

East Asian (EAS) AF: 0.0156 AC: 594 AN: 38046

South Asian (SAS) AF: 0.0191 AC: 1559 AN: 81782

European-Finnish (FIN) AF: 0.0865 AC: 4281 AN: 49472

Middle Eastern (MID) AF: 0.00755 AC: 43 AN: 5694

European-Non Finnish (NFE) AF: 0.0104 AC: 11033 AN: 1064388

Other (OTH) AF: 0.0166 AC: 967 AN: 58144

⚠️ 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: 0.0385 AC: 5675 AN: 147342 Hom.: 160 Cov.: 31 AF XY: 0.0410 AC XY: 2941 AN XY: 71788

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

African (AFR) AF: 0.0361 AC: 1459 AN: 40360

American (AMR) AF: 0.0346 AC: 503 AN: 14552

Ashkenazi Jewish (ASJ) AF: 0.00870 AC: 30 AN: 3448

East Asian (EAS) AF: 0.0339 AC: 170 AN: 5016

South Asian (SAS) AF: 0.0238 AC: 112 AN: 4700

European-Finnish (FIN) AF: 0.118 AC: 1133 AN: 9612

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0320 AC: 2125 AN: 66444

Other (OTH) AF: 0.0333 AC: 68 AN: 2042

⚠️ 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: 0.0312 Hom.: 17

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 23, 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.550-8T>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 206788 control chromosomes in the gnomAD database, including 217 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.550-8T>C in individuals affected with Congenital Adrenal Hyperplasia and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1496017, 15110320). ClinVar contains an entry for this variant (Variation ID: 256295). 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	-0.91
CADD	Benign	2.7
DANN	Benign	0.57
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.040		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: rs1040311; hg19: chr6-32007315; COSMIC: COSV64482182; COSMIC: COSV64482182;