chr9-5304420-T-A

Variant names:

• chr9-5304420-T-A
• rs746620695
• NM_134441.3:c.161A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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. 13/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.75
• Publications: 0 publications found

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]

ENSG00000304317 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134441.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLN2	NM_134441.3	MANE Select	c.161A>T	p.Lys54Ile	missense	Exon 1 of 2	NP_604390.1	P04090-1
	RLN2	NM_005059.4		c.161A>T	p.Lys54Ile	missense	Exon 1 of 3	NP_005050.2
	RLN2	NM_001329191.2		c.-268A>T		upstream_gene	N/A	NP_001316120.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLN2	ENST00000381627.4	TSL:1 MANE Select	c.161A>T	p.Lys54Ile	missense	Exon 1 of 2	ENSP00000371040.3	P04090-1
	RLN2	ENST00000416837.1	TSL:3	c.11A>T	p.Lys4Ile	missense	Exon 1 of 3	ENSP00000399616.1	H0Y5M9
	ENSG00000304317	ENST00000802521.1		n.188+260T>A		intron	N/A

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-1.7
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
PromoterAI		-0.025	Neutral
Varity_R		0.48
gMVP		0.24
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs746620695; hg19: chr9-5304420;