4-47643260-G-A

Variant names:

• chr4-47643260-G-A
• rs55821538
• NM_006587.4:c.1958-4C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006587.4(CORIN):​c.1958-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,588,648 control chromosomes in the GnomAD database, including 509 homozygotes. 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 0.015 (18 hom., cov: 33)
  • Exomes 𝑓: 0.023 (491 hom.)
• Consequence: CORIN NM_006587.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004815
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 5 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)

LOC105374444 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0148 (2253/152254) while in subpopulation NFE AF = 0.0251 (1708/68032). AF 95% confidence interval is 0.0241. There are 18 homozygotes in GnomAd4. There are 1004 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CORIN	NM_006587.4	MANE Select	c.1958-4C>T		splice_region intron	N/A	NP_006578.2
	CORIN	NM_001278585.2		c.1646-4C>T		splice_region intron	N/A	NP_001265514.1
	CORIN	NM_001278586.2		c.1847-4C>T		splice_region intron	N/A	NP_001265515.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CORIN	ENST00000273857.9	TSL:1 MANE Select	c.1958-4C>T		splice_region intron	N/A	ENSP00000273857.4
	CORIN	ENST00000505909.5	TSL:5	c.1847-4C>T		splice_region intron	N/A	ENSP00000425401.1
	CORIN	ENST00000502252.5	TSL:2	c.1757-4C>T		splice_region intron	N/A	ENSP00000424212.1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2254 AN: 152136 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00839

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00727

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0169 AC: 3975 AN: 234796 AF XY: 0.0170

Gnomad AFR exome AF: 0.00331

Gnomad AMR exome AF: 0.00697

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0229 AC: 32836 AN: 1436394 Hom.: 491 Cov.: 31 AF XY: 0.0226 AC XY: 16045 AN XY: 711194

African (AFR) AF: 0.00326 AC: 106 AN: 32560

American (AMR) AF: 0.00684 AC: 275 AN: 40178

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 303 AN: 25030

East Asian (EAS) AF: 0.0000765 AC: 3 AN: 39222

South Asian (SAS) AF: 0.0103 AC: 848 AN: 82412

European-Finnish (FIN) AF: 0.0166 AC: 880 AN: 53078

Middle Eastern (MID) AF: 0.00480 AC: 27 AN: 5630

European-Non Finnish (NFE) AF: 0.0267 AC: 29299 AN: 1098944

Other (OTH) AF: 0.0185 AC: 1095 AN: 59340

GnomAD4 genome AF: 0.0148 AC: 2253 AN: 152254 Hom.: 18 Cov.: 33 AF XY: 0.0135 AC XY: 1004 AN XY: 74428

African (AFR) AF: 0.00399 AC: 166 AN: 41560

American (AMR) AF: 0.00838 AC: 128 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00707 AC: 34 AN: 4808

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1708 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0214 Hom.: 15

Bravo AF: 0.0137

Asia WGS AF: 0.00289 AC: 10 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.032
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

Other links and lift over

dbSNP: rs55821538; hg19: chr4-47645277;