13-31758383-G-C

Variant names:

• chr13-31758383-G-C
• rs200105332
• NM_130806.5:c.220G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130806.5(RXFP2):​c.220G>C​(p.Gly74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RXFP2 NM_130806.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 3 publications found

Genes affected

RXFP2 (HGNC:17318): (relaxin family peptide receptor 2) This gene encodes a member of the GPCR (G protein-coupled, 7-transmembrane receptor) family. Mutations in this gene are associated with cryptorchidism. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

RXFP2 Gene-Disease associations (from GenCC):

• cryptorchidism

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXFP2	NM_130806.5	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 18	ENST00000298386.7	NP_570718.1
RXFP2	NM_001166058.2	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 17		NP_001159530.1
RXFP2	XM_017020389.2	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 15		XP_016875878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXFP2	ENST00000298386.7	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 18	1	NM_130806.5	ENSP00000298386.2
RXFP2	ENST00000380314.2	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 17	1		ENSP00000369670.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33474

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: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.63	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		0.11
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.084	T;T
Sift4G	Benign	0.088	T;T
Polyphen		0.99	.;D
Vest4		0.40
MutPred		0.57		Gain of catalytic residue at G72 (P = 0.0121);Gain of catalytic residue at G72 (P = 0.0121);
MVP		0.93
MPC		0.43
ClinPred		0.89	D
GERP RS		2.8
Varity_R		0.37
gMVP		0.67
Mutation Taster		=64/36	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: rs200105332; hg19: chr13-32332520;