17-63488629-G-C

Variant names:

• chr17-63488629-G-C
• rs4341
• NM_000789.4:c.2306-19G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.2306-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,456,130 control chromosomes in the GnomAD database, including 170,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14062 hom., cov: 25)
  • Exomes 𝑓: 0.48 (170528 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0710
• Publications: 87 publications found

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

ENSG00000264813 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 17-63488629-G-C is Benign according to our data. Variant chr17-63488629-G-C is described in ClinVar as Benign. ClinVar VariationId is 256802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2306-19G>C		intron_variant	Intron 15 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2306-19G>C		intron_variant	Intron 15 of 24	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.584-19G>C		intron_variant	Intron 4 of 30	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 61790 AN: 140006 Hom.: 14038 Cov.: 25

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.403

GnomAD2 exomes AF: 0.501 AC: 125797 AN: 250976 AF XY: 0.500

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.668

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.480 AC: 699193 AN: 1456130 Hom.: 170528 Cov.: 38 AF XY: 0.481 AC XY: 348816 AN XY: 724606

African (AFR) AF: 0.409 AC: 13648 AN: 33404

American (AMR) AF: 0.575 AC: 25683 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9499 AN: 26096

East Asian (EAS) AF: 0.649 AC: 25717 AN: 39646

South Asian (SAS) AF: 0.580 AC: 49972 AN: 86138

European-Finnish (FIN) AF: 0.444 AC: 23563 AN: 53092

Middle Eastern (MID) AF: 0.362 AC: 2084 AN: 5752

European-Non Finnish (NFE) AF: 0.470 AC: 520593 AN: 1107104

Other (OTH) AF: 0.472 AC: 28434 AN: 60200

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.441 AC: 61844 AN: 140112 Hom.: 14062 Cov.: 25 AF XY: 0.440 AC XY: 29904 AN XY: 67978

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

African (AFR) AF: 0.387 AC: 14667 AN: 37894

American (AMR) AF: 0.491 AC: 6701 AN: 13648

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1190 AN: 3326

East Asian (EAS) AF: 0.643 AC: 2908 AN: 4522

South Asian (SAS) AF: 0.562 AC: 2348 AN: 4180

European-Finnish (FIN) AF: 0.408 AC: 3830 AN: 9382

Middle Eastern (MID) AF: 0.304 AC: 85 AN: 280

European-Non Finnish (NFE) AF: 0.452 AC: 28972 AN: 64040

Other (OTH) AF: 0.410 AC: 820 AN: 1998

⚠️ 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: 0.451 Hom.: 2848

Bravo AF: 0.462

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Renal tubular dysgenesis Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		-0.071
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4341; hg19: chr17-61565990;