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GeneBe

9-5304420-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_134441.3(RLN2):c.161A>T(p.Lys54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RLN2
NM_134441.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.75
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.42040837).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RLN2NM_134441.3 linkuse as main transcriptc.161A>T p.Lys54Ile missense_variant 1/2 ENST00000381627.4
RLN2NM_005059.4 linkuse as main transcriptc.161A>T p.Lys54Ile missense_variant 1/3
RLN2XM_047423707.1 linkuse as main transcriptc.113A>T p.Lys38Ile missense_variant 4/5
RLN2XM_047423709.1 linkuse as main transcriptc.-45+1253A>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RLN2ENST00000381627.4 linkuse as main transcriptc.161A>T p.Lys54Ile missense_variant 1/21 NM_134441.3 P1P04090-1
RLN2ENST00000416837.1 linkuse as main transcriptc.14A>T p.Lys5Ile missense_variant 1/33

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000684
AC:
10
AN:
1461476
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
28

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 GeneticsFeb 26, 2024The c.161A>T (p.K54I) alteration is located in exon 1 (coding exon 1) of the RLN2 gene. This alteration results from a A to T substitution at nucleotide position 161, causing the lysine (K) at amino acid position 54 to be replaced by an isoleucine (I). 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
Uncertain
0.46
BayesDel_addAF
Benign
-0.0018
T
BayesDel_noAF
Benign
-0.24
Cadd
Benign
11
Dann
Benign
0.64
DEOGEN2
Uncertain
0.58
D
Eigen
Benign
-0.89
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.42
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
2.0
M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Uncertain
0.30
Sift
Uncertain
0.014
D
Sift4G
Uncertain
0.017
D
Polyphen
0.99
D
Vest4
0.25
MutPred
0.60
Loss of methylation at K54 (P = 0.0116);
MVP
0.51
MPC
0.22
ClinPred
0.86
D
GERP RS
-1.0
Varity_R
0.48
gMVP
0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-5304420; API