rs75770792

Positions:

• chr4-47661782-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006587.4(CORIN):​c.1664C>T​(p.Thr555Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,568 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (75 hom.)
• Consequence: CORIN NM_006587.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.25

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007813364).
• BP6: Variant 4-47661782-G-A is Benign according to our data. Variant chr4-47661782-G-A is described in ClinVar as [Benign]. Clinvar id is 785091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CORIN	NM_006587.4	c.1664C>T	p.Thr555Ile	missense_variant	12/22	ENST00000273857.9
CORIN	NM_001278585.2	c.1352C>T	p.Thr451Ile	missense_variant	10/20
CORIN	NM_001278586.2	c.1553C>T	p.Thr518Ile	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CORIN	ENST00000273857.9	c.1664C>T	p.Thr555Ile	missense_variant	12/22	1	NM_006587.4	P2

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2797 AN: 152194 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00456 AC: 1144 AN: 250680 Hom.: 28 AF XY: 0.00337 AC XY: 456 AN XY: 135466

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00176 AC: 2579 AN: 1461256 Hom.: 75 Cov.: 31 AF XY: 0.00148 AC XY: 1075 AN XY: 726916

Gnomad4 AFR exome AF: 0.0636

Gnomad4 AMR exome AF: 0.00316

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00386

GnomAD4 genome AF: 0.0184 AC: 2799 AN: 152312 Hom.: 93 Cov.: 32 AF XY: 0.0181 AC XY: 1351 AN XY: 74484

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00309 Hom.: 23

Bravo AF: 0.0206

ESP6500AA AF: 0.0626 AC: 276

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00572 AC: 695

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
MetaRNN	Benign	0.0078	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N;.;N;N;N;D
REVEL	Uncertain	0.40
Sift	Benign	0.12	T;.;D;D;D;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.68
MVP		0.92
MPC		0.34
ClinPred		0.030	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs75770792; hg19: chr4-47663799;