rs4646179

Variant names:

• chrX-15566297-A-G
• rs4646179
• NM_001371415.1:c.2070T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001371415.1(ACE2):​c.2070T>C​(p.Asn690Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,209,518 control chromosomes in the GnomAD database, including 101 homozygotes. There are 1,221 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., 527 hem., cov: 23)
  • Exomes 𝑓: 0.0023 (56 hom. 694 hem.)
• Consequence: ACE2 NM_001371415.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0640
• Publications: 7 publications found

Genes affected

ACE2 (HGNC:13557): (angiotensin converting enzyme 2) The protein encoded by this gene belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. This secreted protein catalyzes the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7. ACE2 is known to be expressed in various human organs, and its organ- and cell-specific expression suggests that it may play a role in the regulation of cardiovascular and renal function, as well as fertility. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronavirus HCoV-NL63 and the human severe acute respiratory syndrome coronaviruses, SARS-CoV and SARS-CoV-2, the latter is the causative agent of coronavirus disease-2019 (COVID-19). Multiple splice variants have been found for this gene and the dACE2 (or MIRb-ACE2) splice variant has been found to be interferon inducible. [provided by RefSeq, Nov 2020]

ENSG00000285602 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-15566297-A-G is Benign according to our data. Variant chrX-15566297-A-G is described in ClinVar as Benign. ClinVar VariationId is 778980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.064 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE2	NM_001371415.1	c.2070T>C	p.Asn690Asn	synonymous_variant	Exon 16 of 18	ENST00000252519.8	NP_001358344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE2	ENST00000252519.8	c.2070T>C	p.Asn690Asn	synonymous_variant	Exon 16 of 18	1	NM_001371415.1	ENSP00000252519.3
ENSG00000285602	ENST00000649243.1	n.*1815T>C		non_coding_transcript_exon_variant	Exon 18 of 20			ENSP00000497489.1
ENSG00000285602	ENST00000649243.1	n.*1815T>C		3_prime_UTR_variant	Exon 18 of 20			ENSP00000497489.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2026 AN: 111676 Hom.: 45 Cov.: 23

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00741

Gnomad ASJ AF: 0.00794

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.0113

GnomAD2 exomes AF: 0.00561 AC: 1026 AN: 182741 AF XY: 0.00355

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00231 AC: 2535 AN: 1097790 Hom.: 56 Cov.: 29 AF XY: 0.00191 AC XY: 694 AN XY: 363200

African (AFR) AF: 0.0664 AC: 1753 AN: 26381

American (AMR) AF: 0.00369 AC: 130 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00671 AC: 130 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54087

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40508

Middle Eastern (MID) AF: 0.00580 AC: 24 AN: 4135

European-Non Finnish (NFE) AF: 0.000334 AC: 281 AN: 841846

Other (OTH) AF: 0.00436 AC: 201 AN: 46083

GnomAD4 genome AF: 0.0181 AC: 2026 AN: 111728 Hom.: 45 Cov.: 23 AF XY: 0.0155 AC XY: 527 AN XY: 33928

African (AFR) AF: 0.0615 AC: 1887 AN: 30660

American (AMR) AF: 0.00740 AC: 78 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.00794 AC: 21 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2659

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6099

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.000376 AC: 20 AN: 53152

Other (OTH) AF: 0.0111 AC: 17 AN: 1528

Alfa AF: 0.00810 Hom.: 284

Bravo AF: 0.0218

EpiCase AF: 0.000164

EpiControl AF: 0.000357

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.89
CADD	Benign	0.41
DANN	Benign	0.70
PhyloP100		0.064
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: rs4646179; hg19: chrX-15584420;