chr17-63477132-T-TGCTGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_000789.4(ACE):c.50_55dupCGCTGC(p.Pro17_Leu18dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,420,308 control chromosomes in the GnomAD database, including 161 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L19L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0097 ( 30 hom., cov: 31)

Exomes 𝑓: 0.0055 ( 131 hom. )

Consequence

ACE
NM_000789.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0140

Publications

2 publications found

Variant links:

Genes affected

ACE (HGNC:2707): (angiotensin I converting enzyme) This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]

ACE Gene-Disease associations (from GenCC):

renal tubular dysgenesis - ACE
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
renal tubular dysgenesis of genetic origin
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000789.4

BP6

Variant 17-63477132-T-TGCTGCC is Benign according to our data. Variant chr17-63477132-T-TGCTGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	NM_000789.4	MANE Select	c.50_55dupCGCTGC	p.Pro17_Leu18dup	disruptive_inframe_insertion	Exon 1 of 25	NP_000780.1	P12821-1
ACE	NM_001382700.1		c.-186_-181dupCGCTGC		5_prime_UTR	Exon 1 of 22	NP_001369629.1
ACE	NM_001382701.1		c.-565_-560dupCGCTGC		5_prime_UTR	Exon 1 of 23	NP_001369630.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	ENST00000290866.10	TSL:1 MANE Select	c.50_55dupCGCTGC	p.Pro17_Leu18dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000290866.4	P12821-1
ACE	ENST00000953328.1		c.50_55dupCGCTGC	p.Pro17_Leu18dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000623387.1
ACE	ENST00000884279.1		c.50_55dupCGCTGC	p.Pro17_Leu18dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes

AF:

0.00961

AC:

1451

AN:

150972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00771

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00353

Gnomad SAS

AF:

0.0601

Gnomad FIN

AF:

0.000193

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00916

GnomAD2 exomes

AF:

0.0111

AC:

770

AN:

69620

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.0214

Gnomad AMR exome

AF:

0.00219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00155

Gnomad FIN exome

AF:

0.000222

Gnomad NFE exome

AF:

0.00214

Gnomad OTH exome

AF:

0.00398

GnomAD4 exome

AF:

0.00553

AC:

7020

AN:

1269226

Hom.:

131

Cov.:

AF XY:

0.00658

AC XY:

4110

AN XY:

624786

show subpopulations

African (AFR)

AF:

0.0233

AC:

596

AN:

25628

American (AMR)

AF:

0.00260

AC:

AN:

23420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21196

East Asian (EAS)

AF:

0.00105

AC:

AN:

26788

South Asian (SAS)

AF:

0.0466

AC:

3069

AN:

65904

European-Finnish (FIN)

AF:

0.000501

AC:

AN:

31950

Middle Eastern (MID)

AF:

0.00972

AC:

AN:

3702

European-Non Finnish (NFE)

AF:

0.00282

AC:

2870

AN:

1018854

Other (OTH)

AF:

0.00664

AC:

344

AN:

51784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

280

560

840

1120

1400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00974

AC:

1471

AN:

151082

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

772

AN XY:

73850

show subpopulations

African (AFR)

AF:

0.0204

AC:

843

AN:

41256

American (AMR)

AF:

0.00770

AC:

117

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00354

AC:

AN:

5084

South Asian (SAS)

AF:

0.0597

AC:

287

AN:

4804

European-Finnish (FIN)

AF:

0.000193

AC:

AN:

10372

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00240

AC:

162

AN:

67626

Other (OTH)

AF:

0.0186

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000546

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.014

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over