9-5300138-T-C

Variant names:

• chr9-5300138-T-C
• rs142370960
• NM_134441.3:c.518A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_134441.3(RLN2):​c.518A>G​(p.His173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000629 in 1,605,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: RLN2 NM_134441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.280

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054166198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RLN2	NM_134441.3	c.518A>G	p.His173Arg	missense_variant	Exon 2 of 2	ENST00000381627.4	NP_604390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RLN2	ENST00000381627.4	c.518A>G	p.His173Arg	missense_variant	Exon 2 of 2	1	NM_134441.3	ENSP00000371040.3
RLN2	ENST00000416837	c.*265A>G		3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000399616.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000371 AC: 9 AN: 242330 AF XY: 0.0000383

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000614

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000633 AC: 92 AN: 1452734 Hom.: 0 Cov.: 31 AF XY: 0.0000692 AC XY: 50 AN XY: 722150

Gnomad4 AFR exome AF: 0.0000305 AC: 1 AN: 32776

Gnomad4 AMR exome AF: 0.0000235 AC: 1 AN: 42554

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25786

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39660

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83362

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53294

Gnomad4 NFE exome AF: 0.0000784 AC: 87 AN: 1109560

Gnomad4 Remaining exome AF: 0.0000333 AC: 2 AN: 60014

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74496

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000653 AC: 0.0000653339 AN: 0.0000653339

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000882 AC: 0.0000882016 AN: 0.0000882016

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518A>G (p.H173R) alteration is located in exon 2 (coding exon 2) of the RLN2 gene. This alteration results from a A to G substitution at nucleotide position 518, causing the histidine (H) at amino acid position 173 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.021
DANN	Benign	0.19
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.43	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.072
MVP		0.16
MPC		0.090
ClinPred		0.024	T
GERP RS		-0.33
Varity_R		0.13
gMVP		0.015
Mutation Taster		=91/9	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

Publications

LitVar

Other links and lift over

dbSNP: rs142370960; hg19: chr9-5300138;