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GeneBe

9-5304505-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_134441.3(RLN2):c.76T>A(p.Ser26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,613,070 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.00024 ( 1 hom., cov: 28)
Exomes 𝑓: 0.000080 ( 4 hom. )

Consequence

RLN2
NM_134441.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.711
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04188323).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RLN2NM_134441.3 linkuse as main transcriptc.76T>A p.Ser26Thr missense_variant 1/2 ENST00000381627.4
RLN2NM_005059.4 linkuse as main transcriptc.76T>A p.Ser26Thr missense_variant 1/3
RLN2XM_047423707.1 linkuse as main transcriptc.28T>A p.Ser10Thr missense_variant 4/5
RLN2XM_047423709.1 linkuse as main transcriptc.-45+1168T>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RLN2ENST00000381627.4 linkuse as main transcriptc.76T>A p.Ser26Thr missense_variant 1/21 NM_134441.3 P1P04090-1

Frequencies

GnomAD3 genomes
AF:
0.000244
AC:
37
AN:
151878
Hom.:
1
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.000339
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00260
Gnomad EAS
AF:
0.000387
Gnomad SAS
AF:
0.000624
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000481
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251362
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000801
AC:
117
AN:
1461078
Hom.:
4
Cov.:
31
AF XY:
0.0000839
AC XY:
61
AN XY:
726848
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00104
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000639
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
151992
Hom.:
1
Cov.:
28
AF XY:
0.000215
AC XY:
16
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.000338
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00260
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.000625
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000476
Alfa
AF:
0.0000480
Hom.:
0
ExAC
AF:
0.0000494
AC:
6

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 GeneticsDec 28, 2023The c.76T>A (p.S26T) alteration is located in exon 1 (coding exon 1) of the RLN2 gene. This alteration results from a T to A substitution at nucleotide position 76, causing the serine (S) at amino acid position 26 to be replaced by a threonine (T). 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
0.084
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.71
Cadd
Benign
0.40
Dann
Benign
0.51
DEOGEN2
Benign
0.0076
T
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.0033
N
LIST_S2
Benign
0.21
T
M_CAP
Benign
0.0058
T
MetaRNN
Benign
0.042
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.86
N
REVEL
Benign
0.014
Sift
Benign
0.41
T
Sift4G
Benign
0.26
T
Polyphen
0.0030
B
Vest4
0.083
MVP
0.13
MPC
0.072
ClinPred
0.24
T
GERP RS
-6.0
Varity_R
0.26
gMVP
0.062

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: rs142573027; hg19: chr9-5304505; API