6-24828262-C-T

Position:

• chr6-24828262-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.2540G>A​(p.Arg847Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,548,872 control chromosomes in the GnomAD database, including 35,327 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R847W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (4962 hom., cov: 33)
  • Exomes 𝑓: 0.21 (30365 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.32

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=0.0037442148).
• BP6: Variant 6-24828262-C-T is Benign according to our data. Variant chr6-24828262-C-T is described in ClinVar as [Benign]. Clinvar id is 508154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPOR2	NM_001286445.3	c.2540G>A	p.Arg847Gln	missense_variant	18/22	ENST00000643898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPOR2	ENST00000643898.2	c.2540G>A	p.Arg847Gln	missense_variant	18/22		NM_001286445.3	A2

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36911 AN: 152008 Hom.: 4946 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.201 AC: 31027 AN: 154490 Hom.: 3227 AF XY: 0.196 AC XY: 16043 AN XY: 81934

Gnomad AFR exome AF: 0.357

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.205 AC: 286733 AN: 1396746 Hom.: 30365 Cov.: 33 AF XY: 0.202 AC XY: 139449 AN XY: 688872

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.204

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.243 AC: 36979 AN: 152126 Hom.: 4962 Cov.: 33 AF XY: 0.241 AC XY: 17919 AN XY: 74380

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.219

Alfa AF: 0.203 Hom.: 5548

Bravo AF: 0.256

TwinsUK AF: 0.214 AC: 792

ALSPAC AF: 0.219 AC: 843

ESP6500AA AF: 0.346 AC: 479

ESP6500EA AF: 0.195 AC: 621

ExAC AF: 0.178 AC: 4480

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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.Arg868Gln in exon 19 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 35.59% (748/2102) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs9461073). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -

Autosomal recessive nonsyndromic hearing loss 104 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0058	T;T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0037	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.97	P;P
PrimateAI	Benign	0.22	T
Polyphen		0.13	B;B;B;.;.
Vest4		0.042, 0.047
MPC		0.35
ClinPred		0.0032	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9461073; hg19: chr6-24828490; COSMIC: COSV52418594;