rs61741706

chr6-24828221-C-T

Variant summary

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

The NM_001286445.3(RIPOR2):c.2581G>A(p.Val861Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,551,306 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V861V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (101 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0960

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=0.0019463003).
• BP6: Variant 6-24828221-C-T is Benign according to our data. Variant chr6-24828221-C-T is described in ClinVar as [Benign]. Clinvar id is 508139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPOR2	NM_001286445.3	c.2581G>A	p.Val861Ile	missense_variant	18/22	ENST00000643898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPOR2	ENST00000643898.2	c.2581G>A	p.Val861Ile	missense_variant	18/22		NM_001286445.3	A2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3452 AN: 152100 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00678 AC: 1059 AN: 156134 Hom.: 19 AF XY: 0.00621 AC XY: 514 AN XY: 82752

Gnomad AFR exome AF: 0.0716

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00413

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00480

GnomAD4 exome AF: 0.00471 AC: 6589 AN: 1399088 Hom.: 101 Cov.: 31 AF XY: 0.00449 AC XY: 3098 AN XY: 690046

Gnomad4 AFR exome AF: 0.0754

Gnomad4 AMR exome AF: 0.00748

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00369

Gnomad4 FIN exome AF: 0.000589

Gnomad4 NFE exome AF: 0.00286

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.0227 AC: 3459 AN: 152218 Hom.: 125 Cov.: 32 AF XY: 0.0213 AC XY: 1585 AN XY: 74414

Gnomad4 AFR AF: 0.0723

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00634 Hom.: 34

Bravo AF: 0.0257

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0708 AC: 98

ESP6500EA AF: 0.00220 AC: 7

ExAC AF: 0.00886 AC: 227

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Val882Ile in exon 19 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 7.48% (159/2126) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs61741706). -
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. -

not provided Benign:2

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

RIPOR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.7
Dann	Benign	0.64
DEOGEN2	Benign	0.0075	T;T;T;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.45	N
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.26	T
Polyphen		0.0020	B;B;B;.;.
Vest4		0.10, 0.10
MVP		0.15
MPC		0.25
ClinPred		0.0025	T
GERP RS		-2.9
Varity_R		0.018
gMVP		0.090

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: rs61741706; hg19: chr6-24828449;