chr19-33026609-C-T

Variant names:

• chr19-33026609-C-T
• rs28626308
• NM_033103.5:c.209G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033103.5(RHPN2):​c.209G>A​(p.Arg70Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,607,944 control chromosomes in the GnomAD database, including 5,933 homozygotes. In-silico tool predicts a benign outcome for this variant. 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 Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.072 (529 hom., cov: 31)
  • Exomes 𝑓: 0.067 (5404 hom.)
• Consequence: RHPN2 NM_033103.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

Genes affected

RHPN2 (HGNC:19974): (rhophilin Rho GTPase binding protein 2) This gene encodes a member of the rhophilin family of Ras-homologous (Rho)-GTPase binding proteins. The encoded protein binds both GTP- and GDP-bound RhoA and GTP-bound RhoB and may be involved in the organization of the actin cytoskeleton. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019293427).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHPN2	NM_033103.5	c.209G>A	p.Arg70Gln	missense_variant	Exon 3 of 15	ENST00000254260.8	NP_149094.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHPN2	ENST00000254260.8	c.209G>A	p.Arg70Gln	missense_variant	Exon 3 of 15	1	NM_033103.5	ENSP00000254260.2
RHPN2	ENST00000544458.6	n.663G>A		non_coding_transcript_exon_variant	Exon 1 of 12	2
RHPN2	ENST00000588388.5	n.209G>A		non_coding_transcript_exon_variant	Exon 3 of 14	2		ENSP00000465898.1

Frequencies

GnomAD3 genomes AF: 0.0725 AC: 11011 AN: 151958 Hom.: 528 Cov.: 31

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0859

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0679

GnomAD3 exomes AF: 0.0982 AC: 24323 AN: 247728 Hom.: 1863 AF XY: 0.104 AC XY: 14001 AN XY: 134236

Gnomad AFR exome AF: 0.0683

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.250

Gnomad FIN exome AF: 0.0689

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0885

GnomAD4 exome AF: 0.0669 AC: 97387 AN: 1455868 Hom.: 5404 Cov.: 32 AF XY: 0.0728 AC XY: 52721 AN XY: 724462

Gnomad4 AFR exome AF: 0.0703

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.0709

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.0811

GnomAD4 genome AF: 0.0724 AC: 11011 AN: 152076 Hom.: 529 Cov.: 31 AF XY: 0.0768 AC XY: 5709 AN XY: 74320

Gnomad4 AFR AF: 0.0678

Gnomad4 AMR AF: 0.0856

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.0682

Gnomad4 NFE AF: 0.0533

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0700 Hom.: 112

Bravo AF: 0.0720

TwinsUK AF: 0.0450 AC: 167

ALSPAC AF: 0.0506 AC: 195

ESP6500AA AF: 0.0651 AC: 287

ESP6500EA AF: 0.0543 AC: 467

ExAC AF: 0.0969 AC: 11762

Asia WGS AF: 0.177 AC: 615 AN: 3478

EpiCase AF: 0.0618

EpiControl AF: 0.0631

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.087
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.22
MPC		1.0
ClinPred		0.022	T
GERP RS		2.8
Varity_R		0.23
gMVP		0.44

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: rs28626308; hg19: chr19-33517515; COSMIC: COSV54274321;