X-15592225-C-T

Variant names:

• chrX-15592225-C-T
• rs2285666
• NM_001371415.1:c.439+4G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001371415.1(ACE2):​c.439+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,171,182 control chromosomes in the GnomAD database, including 22,621 homozygotes. There are 83,425 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (2470 hom., 8043 hem., cov: 23)
  • Exomes 𝑓: 0.22 (20151 hom. 75382 hem.)
• Consequence: ACE2 NM_001371415.1 splice_region, intron
• Scores: Splicing: ADA: 0.001385
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 249 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE2	NM_001371415.1	c.439+4G>A		splice_region_variant, intron_variant	Intron 3 of 17	ENST00000252519.8	NP_001358344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE2	ENST00000252519.8	c.439+4G>A		splice_region_variant, intron_variant	Intron 3 of 17	1	NM_001371415.1	ENSP00000252519.3
ENSG00000285602	ENST00000649243.1	n.*517+4G>A		splice_region_variant, intron_variant	Intron 8 of 19			ENSP00000497489.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 26503 AN: 111103 Hom.: 2470 Cov.: 23

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.280 AC: 45478 AN: 162393 AF XY: 0.274

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.547

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.222 AC: 234903 AN: 1060028 Hom.: 20151 Cov.: 22 AF XY: 0.224 AC XY: 75382 AN XY: 336352

African (AFR) AF: 0.219 AC: 5486 AN: 25091

American (AMR) AF: 0.390 AC: 11956 AN: 30672

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 4710 AN: 18416

East Asian (EAS) AF: 0.521 AC: 15436 AN: 29642

South Asian (SAS) AF: 0.440 AC: 21819 AN: 49615

European-Finnish (FIN) AF: 0.191 AC: 7656 AN: 40013

Middle Eastern (MID) AF: 0.220 AC: 871 AN: 3967

European-Non Finnish (NFE) AF: 0.191 AC: 156158 AN: 817950

Other (OTH) AF: 0.242 AC: 10811 AN: 44662

GnomAD4 genome AF: 0.239 AC: 26517 AN: 111154 Hom.: 2470 Cov.: 23 AF XY: 0.241 AC XY: 8043 AN XY: 33434

African (AFR) AF: 0.220 AC: 6746 AN: 30663

American (AMR) AF: 0.368 AC: 3844 AN: 10454

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 686 AN: 2636

East Asian (EAS) AF: 0.526 AC: 1846 AN: 3509

South Asian (SAS) AF: 0.443 AC: 1188 AN: 2681

European-Finnish (FIN) AF: 0.188 AC: 1116 AN: 5950

Middle Eastern (MID) AF: 0.213 AC: 45 AN: 211

European-Non Finnish (NFE) AF: 0.200 AC: 10553 AN: 52859

Other (OTH) AF: 0.237 AC: 359 AN: 1512

Alfa AF: 0.217 Hom.: 9428

Bravo AF: 0.254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.0
DANN	Benign	0.47
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.090
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: rs2285666; hg19: chrX-15610348; COSMIC: COSV53024795; COSMIC: COSV53024795;