NM_130806.5:c.664A>C

Variant names:

• chr13-31777398-A-C
• rs121918303
• NM_130806.5:c.664A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 43 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: Benign. The variant received -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 VariationId is 4159.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130806.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXFP2	NM_130806.5	MANE Select	c.664A>C	p.Thr222Pro	missense	Exon 8 of 18	NP_570718.1
	RXFP2	NM_001166058.2		c.664A>C	p.Thr222Pro	missense	Exon 8 of 17	NP_001159530.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXFP2	ENST00000298386.7	TSL:1 MANE Select	c.664A>C	p.Thr222Pro	missense	Exon 8 of 18	ENSP00000298386.2
	RXFP2	ENST00000380314.2	TSL:1	c.664A>C	p.Thr222Pro	missense	Exon 8 of 17	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

GnomAD2 exomes AF: 0.00458 AC: 1145 AN: 250010 AF XY: 0.00467

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 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

African (AFR) AF: 0.00108 AC: 36 AN: 33428

American (AMR) AF: 0.00457 AC: 204 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 376 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00278 AC: 239 AN: 86052

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53306

Middle Eastern (MID) AF: 0.00579 AC: 33 AN: 5698

European-Non Finnish (NFE) AF: 0.00605 AC: 6716 AN: 1110214

Other (OTH) AF: 0.00599 AC: 361 AN: 60286

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

African (AFR) AF: 0.00106 AC: 44 AN: 41584

American (AMR) AF: 0.00954 AC: 146 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00569 AC: 387 AN: 68032

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00560 Hom.: 7

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Cryptorchidism (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.5
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.025	D
Sift4G	Benign	0.12	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
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121918303; hg19: chr13-32351535;