NM_000497.4:c.1120C>A

Variant names:

• chr8-142875713-G-T
• rs61752786
• NM_000497.4:c.1120C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000497.4(CYP11B1):​c.1120C>A​(p.Arg374Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,594,996 control chromosomes in the GnomAD database, including 413 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (24 hom., cov: 31)
  • Exomes 𝑓: 0.022 (389 hom.)
• Consequence: CYP11B1 NM_000497.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006423
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.175
• Publications: 7 publications found

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B 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 mitochondrial inner membrane and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

GML (HGNC:4375): (glycosylphosphatidylinositol anchored molecule like) Predicted to be involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; apoptotic process; and negative regulation of cell population proliferation. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-142875713-G-T is Benign according to our data. Variant chr8-142875713-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.175 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0217 (2929/135086) while in subpopulation SAS AF = 0.0295 (119/4036). AF 95% confidence interval is 0.0277. There are 24 homozygotes in GnomAd4. There are 1321 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000497.4. 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
	CYP11B1	NM_000497.4	MANE Select	c.1120C>A	p.Arg374Arg	splice_region synonymous	Exon 6 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.1120C>A	p.Arg374Arg	splice_region synonymous	Exon 6 of 8	NP_001021384.1	P15538-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.1120C>A	p.Arg374Arg	splice_region synonymous	Exon 6 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1333C>A	p.Arg445Arg	splice_region synonymous	Exon 8 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.1120C>A	p.Arg374Arg	splice_region synonymous	Exon 6 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 2926 AN: 135006 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00676

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0203

GnomAD2 exomes AF: 0.0174 AC: 4327 AN: 248518 AF XY: 0.0183

Gnomad AFR exome AF: 0.00374

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0220 AC: 32135 AN: 1459910 Hom.: 389 Cov.: 33 AF XY: 0.0219 AC XY: 15915 AN XY: 726290

African (AFR) AF: 0.00390 AC: 130 AN: 33332

American (AMR) AF: 0.00717 AC: 320 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 378 AN: 26070

East Asian (EAS) AF: 0.000305 AC: 12 AN: 39362

South Asian (SAS) AF: 0.0197 AC: 1700 AN: 86202

European-Finnish (FIN) AF: 0.0120 AC: 637 AN: 53228

Middle Eastern (MID) AF: 0.0158 AC: 90 AN: 5714

European-Non Finnish (NFE) AF: 0.0250 AC: 27781 AN: 1111098

Other (OTH) AF: 0.0180 AC: 1087 AN: 60262

GnomAD4 genome AF: 0.0217 AC: 2929 AN: 135086 Hom.: 24 Cov.: 31 AF XY: 0.0201 AC XY: 1321 AN XY: 65738

African (AFR) AF: 0.0141 AC: 482 AN: 34172

American (AMR) AF: 0.0144 AC: 195 AN: 13516

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 56 AN: 3230

East Asian (EAS) AF: 0.0131 AC: 52 AN: 3958

South Asian (SAS) AF: 0.0295 AC: 119 AN: 4036

European-Finnish (FIN) AF: 0.0150 AC: 145 AN: 9654

Middle Eastern (MID) AF: 0.0278 AC: 7 AN: 252

European-Non Finnish (NFE) AF: 0.0288 AC: 1829 AN: 63490

Other (OTH) AF: 0.0201 AC: 38 AN: 1890

Alfa AF: 0.0183 Hom.: 12

EpiCase AF: 0.0234

EpiControl AF: 0.0236

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Deficiency of steroid 11-beta-monooxygenase (2)
-	-	1	Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism (1)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.2
DANN	Benign	0.69
PhyloP100		0.17
PromoterAI		0.056	Neutral
Mutation Taster		=64/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.054
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: rs61752786; hg19: chr8-143957129; COSMIC: COSV52830598;