rs74477879

Positions:

• chr6-24847623-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000259698.9(RIPOR2):​c.1146C>G​(p.Phe382Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,551,674 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (95 hom.)
• Consequence: RIPOR2 ENST00000259698.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.74

Genes affected

RIPOR2 (HGNC:13872): (RHO family interacting cell polarization regulator 2) This gene encodes an atypical inhibitor of the small G protein RhoA. Inhibition of RhoA activity by the encoded protein mediates myoblast fusion and polarization of T cells and neutrophils. The encoded protein is a component of hair cell stereocilia that is essential for hearing. A splice site mutation in this gene results in hearing loss in human patients. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014749169).
• BP6: Variant 6-24847623-G-C is Benign according to our data. Variant chr6-24847623-G-C is described in ClinVar as [Benign]. Clinvar id is 509125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPOR2	NM_001286445.3	c.1164+402C>G		intron_variant		ENST00000643898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1164+402C>G		intron_variant			NM_001286445.3	A2

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3254 AN: 152196 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00515 AC: 805 AN: 156436 Hom.: 15 AF XY: 0.00438 AC XY: 363 AN XY: 82874

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.000179

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00356 AC: 4980 AN: 1399360 Hom.: 95 Cov.: 31 AF XY: 0.00322 AC XY: 2223 AN XY: 690188

Gnomad4 AFR exome AF: 0.0756

Gnomad4 AMR exome AF: 0.00504

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.0214 AC: 3261 AN: 152314 Hom.: 125 Cov.: 32 AF XY: 0.0198 AC XY: 1477 AN XY: 74476

Gnomad4 AFR AF: 0.0718

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00464 Hom.: 12

Bravo AF: 0.0244

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.00724 AC: 188

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.00069	T;T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Benign	0.37	T
Polyphen		0.0	B;B;B;.
Vest4		0.081, 0.069
MutPred		0.31		Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);
MVP		0.10
MPC		0.35
ClinPred		0.0087	T
GERP RS		4.3
Varity_R		0.089
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74477879; hg19: chr6-24847851; COSMIC: COSV52419202; COSMIC: COSV52419202;