9-5300385-C-G

Position:

• chr9-5300385-C-G

Variant summary

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

The NM_134441.3(RLN2):​c.271G>C​(p.Val91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,612,752 control chromosomes in the GnomAD database, including 1 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 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: RLN2 NM_134441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0800

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=0.008643895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLN2	NM_134441.3	c.271G>C	p.Val91Leu	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.271G>C	p.Val91Leu	missense_variant	2/2	1	NM_134441.3	ENSP00000371040	P1
RLN2	ENST00000416837.1	c.*18G>C		3_prime_UTR_variant	3/3	3		ENSP00000399616

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000533 AC: 133 AN: 249426 Hom.: 0 AF XY: 0.000668 AC XY: 90 AN XY: 134674

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000620 AC: 906 AN: 1460712 Hom.: 1 Cov.: 31 AF XY: 0.000621 AC XY: 451 AN XY: 726536

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000786

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000657

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000487 AC: 74 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74310

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000645 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00148

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

Sep 15, 2021

The c.271G>C (p.V91L) alteration is located in exon 2 (coding exon 2) of the RLN2 gene. This alteration results from a G to C substitution at nucleotide position 271, causing the valine (V) at amino acid position 91 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.6
DANN	Benign	0.79
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.040	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.0
Sift	Benign	0.30	T
Sift4G	Benign	0.40	T
Polyphen		0.0030	B
Vest4		0.086
MVP		0.040
MPC		0.076
ClinPred		0.0011	T
GERP RS		-3.0
Varity_R		0.051
gMVP		0.052

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs148022171; hg19: chr9-5300385;