9-5300183-C-A

Variant names:

• chr9-5300183-C-A
• rs767650831
• NM_134441.3:c.473G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_134441.3(RLN2):​c.473G>T​(p.Arg158Leu) 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 1,460,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RLN2 NM_134441.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134441.3. 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
	RLN2	NM_134441.3	MANE Select	c.473G>T	p.Arg158Leu	missense	Exon 2 of 2	NP_604390.1	P04090-1
	RLN2	NM_001329191.2		c.218G>T	p.Arg73Leu	missense	Exon 2 of 2	NP_001316120.1
	RLN2	NM_005059.4		c.*220G>T		3_prime_UTR	Exon 3 of 3	NP_005050.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLN2	ENST00000381627.4	TSL:1 MANE Select	c.473G>T	p.Arg158Leu	missense	Exon 2 of 2	ENSP00000371040.3	P04090-1
	RLN2	ENST00000416837.1	TSL:3	c.*220G>T		3_prime_UTR	Exon 3 of 3	ENSP00000399616.1	H0Y5M9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250244 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460270 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726420

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111510

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.7
DANN	Benign	0.97
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.061
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.23
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.012	D
Polyphen		0.21	B
Vest4		0.20
MutPred		0.76		Loss of MoRF binding (P = 0.0059)
MVP		0.59
MPC		0.18
ClinPred		0.22	T
GERP RS		1.4
Varity_R		0.31
gMVP		0.076
Mutation Taster		=97/3	polymorphism

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: rs767650831; hg19: chr9-5300183;