rs121918303

Positions:

• chr13-31777398-A-C
• chr13-31777398-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_130806.5(RXFP2):​c.664A>C​(p.Thr222Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,611,690 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (26 hom.)
• Consequence: RXFP2 NM_130806.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.48

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011102617).
• BP6: Variant 13-31777398-A-C is Benign according to our data. Variant chr13-31777398-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4159.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 701 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RXFP2	NM_130806.5	c.664A>C	p.Thr222Pro	missense_variant	8/18	ENST00000298386.7	NP_570718.1
RXFP2	NM_001166058.2	c.664A>C	p.Thr222Pro	missense_variant	8/17		NP_001159530.1
RXFP2	XM_017020389.2	c.664A>C	p.Thr222Pro	missense_variant	8/15		XP_016875878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RXFP2	ENST00000298386.7	c.664A>C	p.Thr222Pro	missense_variant	8/18	1	NM_130806.5	ENSP00000298386.2
RXFP2	ENST00000380314.2	c.664A>C	p.Thr222Pro	missense_variant	8/17	1		ENSP00000369670.1

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152226 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00569

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00458 AC: 1145 AN: 250010 Hom.: 3 AF XY: 0.00467 AC XY: 631 AN XY: 135106

Gnomad AFR exome AF: 0.000990

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00299

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00690

GnomAD4 exome AF: 0.00551 AC: 8042 AN: 1459346 Hom.: 26 Cov.: 29 AF XY: 0.00543 AC XY: 3941 AN XY: 725978

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00457

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00278

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00605

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.00460 AC: 701 AN: 152344 Hom.: 5 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74500

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00569

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00587 Hom.: 4

Bravo AF: 0.00463

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00617 AC: 53

ExAC AF: 0.00440 AC: 534

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00715

EpiControl AF: 0.00748

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RXFP2: BP4, BS2 -

Cryptorchidism Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.20	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.025	D;T
Sift4G	Benign	0.12	T;T
Polyphen		0.74	.;P
Vest4		0.44
MVP		0.89
MPC		0.38
ClinPred		0.060	T
GERP RS		3.8
Varity_R		0.32
gMVP		0.71

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: rs121918303; hg19: chr13-32351535;