Variant 9-5304394-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_134441.3(RLN2):c.187C>G(p.Pro63Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.0000014 ( 1 hom. )

Consequence

RLN2
NM_134441.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.71

Variant links:

Genes affected

RLN2 (HGNC:10027): (relaxin 2) This gene encodes a member of the relaxin subfamily and insulin superfamily of peptide hormones. In humans there are three non-allelic relaxin genes. This gene encodes multiple protein isoforms, at least one of which undergoes proteolytic processing. This processing generates relaxin A and B chains that are linked by disulfide bonds to form the mature peptide hormone. This hormone plays a role in the male and female reproductive systems and was initially noted for its role in pregnancy. This protein also plays broader roles in the cardiovascular system, including in the regulation of blood pressure and control of heart rate, and data from animal models shows that this protein may have anti-fibrotic and cardioprotective effects. [provided by RefSeq, Jul 2016]

RLN2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.064508736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLN2	NM_134441.3 linkuse as main transcript	c.187C>G	p.Pro63Ala	missense_variant	1/2	ENST00000381627.4	NP_604390.1	P04090-1
RLN2	NM_005059.4 linkuse as main transcript	c.187C>G	p.Pro63Ala	missense_variant	1/3		NP_005050.2	P04090-2
RLN2	XM_047423707.1 linkuse as main transcript	c.139C>G	p.Pro47Ala	missense_variant	4/5		XP_047279663.1
RLN2	XM_047423709.1 linkuse as main transcript	c.-45+1279C>G		intron_variant			XP_047279665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLN2	ENST00000381627.4 linkuse as main transcript	c.187C>G	p.Pro63Ala	missense_variant	1/2	1	NM_134441.3	ENSP00000371040.3		P04090-1
RLN2	ENST00000416837.1 linkuse as main transcript	c.37C>G	p.Pro13Ala	missense_variant	1/3	3		ENSP00000399616.1		H0Y5M9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248902

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459156

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725946

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.187C>G (p.P63A) alteration is located in exon 1 (coding exon 1) of the RLN2 gene. This alteration results from a C to G substitution at nucleotide position 187, causing the proline (P) at amino acid position 63 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.0030

DANN

Benign

0.48

DEOGEN2

Benign

0.21

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.45

M_CAP

Benign

0.0078

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.84

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.55

Polyphen

0.0070

Vest4

0.092

MutPred

0.41

Loss of disorder (P = 0.0918);

MVP

0.055

MPC

0.077

ClinPred

0.050

GERP RS

-6.4

Varity_R

0.037

gMVP

0.10

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over