19-33026609-C-A

Position:

• chr19-33026609-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033103.5(RHPN2):​c.209G>T​(p.Arg70Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHPN2	NM_033103.5	c.209G>T	p.Arg70Leu	missense_variant	3/15	ENST00000254260.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHPN2	ENST00000254260.8	c.209G>T	p.Arg70Leu	missense_variant	3/15	1	NM_033103.5	P1
RHPN2	ENST00000544458.6	n.663G>T		non_coding_transcript_exon_variant	1/12	2
RHPN2	ENST00000588388.5	c.209G>T	p.Arg70Leu	missense_variant, NMD_transcript_variant	3/14	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.70
MutPred		0.66		Loss of MoRF binding (P = 0.0114);
MVP		0.47
MPC		1.2
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.61
gMVP		0.58

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;