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GeneBe

9-5300223-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.115
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]

Genome browser will be placed here

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=0.015596479).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RLN2NM_134441.3 linkuse as main transcriptc.433C>T p.Pro145Ser missense_variant 2/2 ENST00000381627.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RLN2ENST00000381627.4 linkuse as main transcriptc.433C>T p.Pro145Ser missense_variant 2/21 NM_134441.3 P1P04090-1
RLN2ENST00000416837.1 linkuse as main transcriptc.*180C>T 3_prime_UTR_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.000664
AC:
101
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 26, 2021The 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

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

Other links and lift over

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