chr19-32991915-G-A

Position:

• chr19-32991915-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_033103.5(RHPN2):​c.1552C>T​(p.Arg518Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,896 control chromosomes in the GnomAD database, including 1,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (121 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1737 hom.)
• Consequence: RHPN2 NM_033103.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.91

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 -18 ACMG points.

• PM1: In a mutagenesis_site Does not induce actin disassembly but still interacts with RhoA; when associated with A-526 and A-527. (size 0) in uniprot entity RHPN2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017555058).
• BP6: Variant 19-32991915-G-A is Benign according to our data. Variant chr19-32991915-G-A is described in ClinVar as [Benign]. Clinvar id is 403376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHPN2	NM_033103.5	c.1552C>T	p.Arg518Cys	missense_variant	13/15	ENST00000254260.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHPN2	ENST00000254260.8	c.1552C>T	p.Arg518Cys	missense_variant	13/15	1	NM_033103.5	P1
RHPN2	ENST00000544458.6	n.1881C>T		non_coding_transcript_exon_variant	10/12	2
RHPN2	ENST00000591502.1	n.231C>T		non_coding_transcript_exon_variant	1/2	2
RHPN2	ENST00000588388.5	c.*1089C>T		3_prime_UTR_variant, NMD_transcript_variant	12/14	2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4295 AN: 152158 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0453 AC: 11362 AN: 251002 Hom.: 511 AF XY: 0.0507 AC XY: 6877 AN XY: 135680

Gnomad AFR exome AF: 0.00592

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0133

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0320

Gnomad OTH exome AF: 0.0485

GnomAD4 exome AF: 0.0360 AC: 52677 AN: 1461620 Hom.: 1737 Cov.: 31 AF XY: 0.0397 AC XY: 28897 AN XY: 727112

Gnomad4 AFR exome AF: 0.00565

Gnomad4 AMR exome AF: 0.0441

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.0144

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0284

Gnomad4 OTH exome AF: 0.0424

GnomAD4 genome AF: 0.0282 AC: 4300 AN: 152276 Hom.: 121 Cov.: 32 AF XY: 0.0297 AC XY: 2210 AN XY: 74454

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.0398

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0310

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0351 Hom.: 51

Bravo AF: 0.0262

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0342 AC: 294

ExAC AF: 0.0455 AC: 5520

Asia WGS AF: 0.0730 AC: 254 AN: 3478

EpiCase AF: 0.0391

EpiControl AF: 0.0413

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.037
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Polyphen		0.0050	B
Vest4		0.089
MPC		0.45
ClinPred		0.0061	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.45

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: rs79314177; hg19: chr19-33482821; COSMIC: COSV54274939; COSMIC: COSV54274939;