Genetic Variant ACE:c.2306-105_2306-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT (chr17-63488529-T-TATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000789.4(ACE):c.2306-105_2306-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT variant causes a intron change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Uncertain Significance (★★★).

Frequency

Genomes: not found (cov: 27)

Consequence

ACE
NM_000789.4 intron

Scores

Not classified

Clinical Significance

drug response reviewed by expert panel U:1O:1

Conservation

PhyloP100: -1.31

Publications

326 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), PanelApp Australia
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

ENSG00000264813 (HGNC:):

ENSG00000264813 links:

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new If you want to explore the variant's impact on the transcript NM_000789.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
ACE NM_000789.4	MANE Select	c.2306-105_2306-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT	intron	Intron 15 of 24	Prot: NP_000780.1 UniProt: P12821-1
ACE NM_001382700.1		c.1739-105_1739-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT	intron	Intron 12 of 21	Prot: NP_001369629.1
ACE NM_001382701.1		c.1454-105_1454-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT	intron	Intron 13 of 22	Prot: NP_001369630.1

ACE NM_000789.4

MANE Select

HGVSc / HGVSpc.2306-105_2306-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT

Exon rankIntron 15 of 24

intron

Prot: NP_000780.1UniProt: P12821-1

ACE NM_001382700.1

HGVSc / HGVSpc.1739-105_1739-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT

Exon rankIntron 12 of 21

intron

Prot: NP_001369629.1

ACE NM_001382701.1

HGVSc / HGVSpc.1454-105_1454-104insTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCATACAGTCACTTTT

Exon rankIntron 13 of 22

intron

Prot: NP_001369630.1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
ACE ENST00000290866.10	TSL:1MANE Select	c.2306-119_2306-118insATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC	intron	Intron 15 of 24	Prot: ENSP00000290866.4 UniProt: P12821-1
ACE ENST00000290863.10	TSL:1	c.584-119_584-118insATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC	intron	Intron 4 of 13	Prot: ENSP00000290863.6 UniProt: P12821-3
ENSG00000264813 ENST00000577647.2	TSL:2	n.584-119_584-118insATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC	intron	Intron 4 of 30	Prot: ENSP00000464149.1 UniProt: F6X3S4

ACE ENST00000290866.10

TSL:1MANE Select

HGVSc / HGVSpc.2306-119_2306-118insATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC

Exon rankIntron 15 of 24

intron

Prot: ENSP00000290866.4UniProt: P12821-1

ACE ENST00000290863.10

TSL:1

HGVSc / HGVSpc.584-119_584-118insATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC

Exon rankIntron 4 of 13

intron

Prot: ENSP00000290863.6UniProt: P12821-3

ENSG00000264813 ENST00000577647.2

TSL:2

HGVSc / HGVSpn.584-119_584-118insATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC

Exon rankIntron 4 of 30

intron

Prot: ENSP00000464149.1UniProt: F6X3S4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:27
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:13
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:27

Showing 3 sources

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Risk of requirement of invasive mechanical ventilation in patients with severe COVID-19 (1)

captopril response - Efficacy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	-1.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence