Genetic Variant NM_006587.4:c.2947G>A (chr4-47595903-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006587.4(CORIN):c.2947G>A(p.Gly983Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CORIN
NM_006587.4 missense, splice_region

Scores

Splicing: ADA: 0.9994

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70

Publications

0 publications found

Variant links:

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)

CORIN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006587.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CORIN	NM_006587.4	MANE Select	c.2947G>A	p.Gly983Ser	missense splice_region	Exon 22 of 22	NP_006578.2
	CORIN	NM_001278585.2		c.2635G>A	p.Gly879Ser	missense splice_region	Exon 20 of 20	NP_001265514.1	A0A087X1D5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CORIN	ENST00000273857.9	TSL:1 MANE Select	c.2947G>A	p.Gly983Ser	missense splice_region	Exon 22 of 22	ENSP00000273857.4	Q9Y5Q5-1
CORIN	ENST00000961995.1		c.3022G>A	p.Gly1008Ser	missense splice_region	Exon 23 of 23	ENSP00000632054.1
CORIN	ENST00000961980.1		c.2929G>A	p.Gly977Ser	missense splice_region	Exon 22 of 22	ENSP00000632039.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454492

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32784

American (AMR)

AF:

0.00

AC:

AN:

42800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

85188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109606

Other (OTH)

AF:

0.00

AC:

AN:

59926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

7.7

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.82

Vest4

0.90

MutPred

0.90

Loss of glycosylation at S985 (P = 0.0439)

MVP

1.0

MPC

0.36

ClinPred

1.0

GERP RS

5.2

Varity_R

0.70

gMVP

0.85

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over