4-47786656-G-T

Variant names:

• chr4-47786656-G-T
• rs74701656
• NM_006587.4:c.409+69C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006587.4(CORIN):​c.409+69C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000941 in 1,062,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: CORIN NM_006587.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CORIN	NM_006587.4	c.409+69C>A		intron_variant	Intron 3 of 21	ENST00000273857.9	NP_006578.2
CORIN	NM_001278585.2	c.208+20247C>A		intron_variant	Intron 2 of 19		NP_001265514.1
CORIN	NM_001278586.2	c.409+69C>A		intron_variant	Intron 3 of 13		NP_001265515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CORIN	ENST00000273857.9	c.409+69C>A		intron_variant	Intron 3 of 21	1	NM_006587.4	ENSP00000273857.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.41e-7 AC: 1 AN: 1062144 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 541406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24736

American (AMR) AF: 0.00 AC: 0 AN: 36042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21272

East Asian (EAS) AF: 0.00 AC: 0 AN: 37620

South Asian (SAS) AF: 0.00 AC: 0 AN: 71036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.00000130 AC: 1 AN: 767862

Other (OTH) AF: 0.00 AC: 0 AN: 46958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.12
DANN	Benign	0.61
PhyloP100		-1.3

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: rs74701656; hg19: chr4-47788673;