rs281865544

Variant names:

• chr6-32040421-C-T
• rs7755898
• NM_000500.9:c.955C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32040421-C-T
• chrNT_113891.3-3478743-C-T
• chrNT_167245.2-3281829-C-T
• chrNT_167247.2-3382454-C-T
• chrNT_167249.2-3341608-C-T
• chr6-32040421-C-G
• chrNT_113891.3-3478743-C-G
• chrNT_167245.2-3281829-C-G
• chrNT_167247.2-3382454-C-G
• chrNT_167249.2-3341608-C-G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.955C>T​(p.Gln319*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000896 in 1,580,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002107127: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:3267225) - PS3."" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:28 O:1
• Conservation: PhyloP100: 0.664
• Publications: 90 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002107127: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 3267225) - PS3."; SCV005397349: A functiol study has confirmed that mR of this variant is rapidly degraded when expressed in mammalian cells (PMID: 3267225).; SCV000841754: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 3267225)
• PP5: Variant 6-32040421-C-T is Pathogenic according to our data. Variant chr6-32040421-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. 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
	CYP21A2	NM_000500.9	MANE Select	c.955C>T	p.Gln319*	stop_gained	Exon 8 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.865C>T	p.Gln289*	stop_gained	Exon 7 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.550C>T	p.Gln184*	stop_gained	Exon 8 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.955C>T	p.Gln319*	stop_gained	Exon 8 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.991C>T	p.Gln331*	stop_gained	Exon 8 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.964C>T	p.Gln322*	stop_gained	Exon 8 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 523 AN: 136986 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00878

Gnomad EAS AF: 0.00236

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.000399

Gnomad MID AF: 0.0534

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 249104 AF XY: 0.0000815

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000622 AC: 898 AN: 1443134 Hom.: 0 Cov.: 38 AF XY: 0.000684 AC XY: 491 AN XY: 717354

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

African (AFR) AF: 0.000491 AC: 16 AN: 32566

American (AMR) AF: 0.000907 AC: 40 AN: 44094

Ashkenazi Jewish (ASJ) AF: 0.00292 AC: 74 AN: 25326

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39132

South Asian (SAS) AF: 0.000713 AC: 60 AN: 84116

European-Finnish (FIN) AF: 0.000154 AC: 8 AN: 51994

Middle Eastern (MID) AF: 0.00416 AC: 23 AN: 5534

European-Non Finnish (NFE) AF: 0.000534 AC: 588 AN: 1101314

Other (OTH) AF: 0.00141 AC: 83 AN: 59058

⚠️ 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: 0.00378 AC: 518 AN: 137118 Hom.: 0 Cov.: 33 AF XY: 0.00381 AC XY: 255 AN XY: 67010

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

African (AFR) AF: 0.00333 AC: 119 AN: 35752

American (AMR) AF: 0.00419 AC: 58 AN: 13852

Ashkenazi Jewish (ASJ) AF: 0.00878 AC: 28 AN: 3190

East Asian (EAS) AF: 0.00237 AC: 11 AN: 4646

South Asian (SAS) AF: 0.0126 AC: 51 AN: 4058

European-Finnish (FIN) AF: 0.000399 AC: 4 AN: 10034

Middle Eastern (MID) AF: 0.0407 AC: 10 AN: 246

European-Non Finnish (NFE) AF: 0.00346 AC: 217 AN: 62642

Other (OTH) AF: 0.0108 AC: 20 AN: 1846

⚠️ 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: 0.00853 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
16	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (17)
10	-	-	not provided (10)
1	-	-	Congenital adrenal hyperplasia (1)
1	-	-	CYP21A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		0.66
Vest4		0.83
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7755898; hg19: chr6-32008198; COSMIC: COSV64480175; COSMIC: COSV64480175;