9-5300223-G-A

Position:

• chr9-5300223-G-A

Variant summary

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

The NM_134441.3(RLN2):​c.433C>T​(p.Pro145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,613,824 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: RLN2 NM_134441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.115

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015596479).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLN2	NM_134441.3	c.433C>T	p.Pro145Ser	missense_variant	2/2	ENST00000381627.4	NP_604390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLN2	ENST00000381627.4	c.433C>T	p.Pro145Ser	missense_variant	2/2	1	NM_134441.3	ENSP00000371040	P1
RLN2	ENST00000416837.1	c.*180C>T		3_prime_UTR_variant	3/3	3		ENSP00000399616

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000788 AC: 198 AN: 251376 Hom.: 0 AF XY: 0.000684 AC XY: 93 AN XY: 135868

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000863 AC: 1262 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.000839 AC XY: 610 AN XY: 727134

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000954

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74412

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.000650

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000758 AC: 92

EpiCase AF: 0.000764

EpiControl AF: 0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.433C>T (p.P145S) alteration is located in exon 2 (coding exon 2) of the RLN2 gene. This alteration results from a C to T substitution at nucleotide position 433, causing the proline (P) at amino acid position 145 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.3
DANN	Benign	0.19
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.20
Sift	Benign	0.55	T
Sift4G	Benign	0.66	T
Polyphen		0.14	B
Vest4		0.094
MVP		0.49
MPC		0.080
ClinPred		0.014	T
GERP RS		2.1
Varity_R		0.064
gMVP		0.072

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

Other links and lift over

dbSNP: rs151289366; hg19: chr9-5300223; COSMIC: COSV57732083;