chr4-47665047-T-C

Variant names:

• chr4-47665047-T-C
• rs11934749
• NM_006587.4:c.1574A>G

Variant summary

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

The NM_006587.4(CORIN):​c.1574A>G​(p.His525Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,606,500 control chromosomes in the GnomAD database, including 608,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H525Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.90 (61460 hom., cov: 31)
  • Exomes 𝑓: 0.87 (546882 hom.)
• Consequence: CORIN NM_006587.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 38 publications found

Genes affected

CORIN (HGNC:19012): (corin, serine peptidase) This gene encodes a member of the type II transmembrane serine protease class of the trypsin superfamily. Members of this family are composed of multiple structurally distinct domains. The encoded protein converts pro-atrial natriuretic peptide to biologically active atrial natriuretic peptide, a cardiac hormone that regulates blood volume and pressure. This protein may also function as a pro-brain-type natriuretic peptide convertase. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

CORIN Gene-Disease associations (from GenCC):

• preeclampsia/eclampsia 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1556474E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CORIN	NM_006587.4	c.1574A>G	p.His525Arg	missense_variant	Exon 11 of 22	ENST00000273857.9	NP_006578.2
CORIN	NM_001278585.2	c.1262A>G	p.His421Arg	missense_variant	Exon 9 of 20		NP_001265514.1
CORIN	NM_001278586.2	c.1463A>G	p.His488Arg	missense_variant	Exon 10 of 14		NP_001265515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CORIN	ENST00000273857.9	c.1574A>G	p.His525Arg	missense_variant	Exon 11 of 22	1	NM_006587.4	ENSP00000273857.4

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136271 AN: 152082 Hom.: 61390 Cov.: 31

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.880

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.870

GnomAD2 exomes AF: 0.874 AC: 218957 AN: 250642 AF XY: 0.865

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.977

Gnomad FIN exome AF: 0.918

Gnomad NFE exome AF: 0.861

Gnomad OTH exome AF: 0.854

GnomAD4 exome AF: 0.866 AC: 1259384 AN: 1454300 Hom.: 546882 Cov.: 33 AF XY: 0.863 AC XY: 624696 AN XY: 723958

African (AFR) AF: 0.978 AC: 32565 AN: 33310

American (AMR) AF: 0.902 AC: 40307 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18363 AN: 26068

East Asian (EAS) AF: 0.972 AC: 38478 AN: 39600

South Asian (SAS) AF: 0.796 AC: 68567 AN: 86088

European-Finnish (FIN) AF: 0.917 AC: 48938 AN: 53388

Middle Eastern (MID) AF: 0.779 AC: 4478 AN: 5750

European-Non Finnish (NFE) AF: 0.865 AC: 955923 AN: 1105218

Other (OTH) AF: 0.860 AC: 51765 AN: 60176

GnomAD4 genome AF: 0.896 AC: 136401 AN: 152200 Hom.: 61460 Cov.: 31 AF XY: 0.896 AC XY: 66629 AN XY: 74396

African (AFR) AF: 0.976 AC: 40560 AN: 41560

American (AMR) AF: 0.880 AC: 13446 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2421 AN: 3468

East Asian (EAS) AF: 0.973 AC: 5026 AN: 5164

South Asian (SAS) AF: 0.804 AC: 3868 AN: 4808

European-Finnish (FIN) AF: 0.917 AC: 9717 AN: 10594

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58503 AN: 68012

Other (OTH) AF: 0.872 AC: 1846 AN: 2116

Alfa AF: 0.864 Hom.: 179374

Bravo AF: 0.899

TwinsUK AF: 0.859 AC: 3187

ALSPAC AF: 0.860 AC: 3316

ESP6500AA AF: 0.972 AC: 4281

ESP6500EA AF: 0.849 AC: 7302

ExAC AF: 0.876 AC: 106345

Asia WGS AF: 0.905 AC: 3149 AN: 3478

EpiCase AF: 0.848

EpiControl AF: 0.844

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.6
DANN	Benign	0.16
DEOGEN2	Benign	0.065	T;.;.;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.077	T;T;T;T;T;T
MetaRNN	Benign	0.0000012	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	N;.;.;.;.;.
PhyloP100		1.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.8	N;.;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;.;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.067
MPC		0.065
ClinPred		0.0051	T
GERP RS		4.3
Varity_R		0.058
gMVP		0.33
Mutation Taster		=99/1	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: rs11934749; hg19: chr4-47667064; COSMIC: COSV107268348; COSMIC: COSV107268348;