rs12709426

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000789.4(ACE):c.1775A>G(p.Asp592Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,612,002 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D592N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 60 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 46 hom. )

Consequence

ACE
NM_000789.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.64

Publications

18 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 of genetic origin
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant 17-63484395-A-G is Benign according to our data. Variant chr17-63484395-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2182/152320) while in subpopulation AFR AF = 0.0502 (2087/41582). AF 95% confidence interval is 0.0484. There are 60 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.1775A>G	p.Asp592Gly	missense_variant	Exon 12 of 25	ENST00000290866.10	NP_000780.1	P12821-1B4DKH4
ACE	NM_001382700.1 link	c.1208A>G	p.Asp403Gly	missense_variant	Exon 9 of 22		NP_001369629.1
ACE	NM_001382701.1 link	c.923A>G	p.Asp308Gly	missense_variant	Exon 10 of 23		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 link	c.1775A>G	p.Asp592Gly	missense_variant	Exon 12 of 25	1	NM_000789.4	ENSP00000290866.4		P12821-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2177

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00382

AC:

945

AN:

247268

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.0509

Gnomad AMR exome

AF:

0.00311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00159

AC:

2314

AN:

1459682

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

979

AN XY:

726120

show subpopulations

African (AFR)

AF:

0.0515

AC:

1723

AN:

33446

American (AMR)

AF:

0.00334

AC:

149

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000128

AC:

AN:

86040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52484

Middle Eastern (MID)

AF:

0.00137

AC:

AN:

5118

European-Non Finnish (NFE)

AF:

0.000189

AC:

210

AN:

1111856

Other (OTH)

AF:

0.00355

AC:

214

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

143

286

430

573

716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0143

AC:

2182

AN:

152320

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1012

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0502

AC:

2087

AN:

41582

American (AMR)

AF:

0.00399

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68014

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00503

Hom.:

Bravo

AF:

0.0159

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0486

AC:

214

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00465

AC:

564

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ACE-related disorder

Benign:1

Oct 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Renal tubular dysgenesis

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.020

T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L

PhyloP100

1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.076

Sift

Benign

0.36

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0010

.;B

Vest4

0.19

MVP

0.47

MPC

0.12

ClinPred

0.0096

GERP RS

3.9

PromoterAI

0.0034

Neutral

(source)

Varity_R

0.24

gMVP

0.33

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: 0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over