9-5304563-A-C

Position:

• chr9-5304563-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_134441.3(RLN2):​c.18T>G​(p.Phe6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,613,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: RLN2 NM_134441.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.644

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007293761).
• BP6: Variant 9-5304563-A-C is Benign according to our data. Variant chr9-5304563-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2353825.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLN2	NM_134441.3	c.18T>G	p.Phe6Leu	missense_variant	1/2	ENST00000381627.4	NP_604390.1
RLN2	NM_005059.4	c.18T>G	p.Phe6Leu	missense_variant	1/3		NP_005050.2
RLN2	XM_047423707.1	c.15-45T>G		intron_variant			XP_047279663.1
RLN2	XM_047423709.1	c.-45+1110T>G		intron_variant			XP_047279665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLN2	ENST00000381627.4	c.18T>G	p.Phe6Leu	missense_variant	1/2	1	NM_134441.3	ENSP00000371040	P1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151846 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251086 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135766

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000654

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1461254 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 146 AN XY: 726922

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000858

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151964 Hom.: 0 Cov.: 28 AF XY: 0.000135 AC XY: 10 AN XY: 74296

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.1
DANN	Benign	0.76
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00027	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MutPred		0.39		Loss of catalytic residue at F6 (P = 0.014);
MVP		0.048
MPC		0.085
ClinPred		0.0059	T
GERP RS		-0.28
Varity_R		0.055
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764578089; hg19: chr9-5304563;