6-24828262-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.32

Publications

20 publications found

Variant links:

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]

RIPOR2 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 104
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nonsyndromic hearing loss 21
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RIPOR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3 link	c.2540G>A	p.Arg847Gln	missense_variant	Exon 18 of 22	ENST00000643898.2	NP_001273374.1	A0A2R8YEE0B7Z5J9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2 link	c.2540G>A	p.Arg847Gln	missense_variant	Exon 18 of 22		NM_001286445.3	ENSP00000494268.2		A0A2R8YEE0

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36911

AN:

152008

Hom.:

4946

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.201

AC:

31027

AN:

154490

AF XY:

0.196

show subpopulations

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 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.:

AF XY:

0.202

AC XY:

139449

AN XY:

688872

show subpopulations

African (AFR)

AF:

0.364

AC:

11460

AN:

31444

American (AMR)

AF:

0.217

AC:

7720

AN:

35526

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

5740

AN:

25124

East Asian (EAS)

AF:

0.207

AC:

7355

AN:

35610

South Asian (SAS)

AF:

0.147

AC:

11623

AN:

78986

European-Finnish (FIN)

AF:

0.192

AC:

9454

AN:

49186

Middle Eastern (MID)

AF:

0.192

AC:

1088

AN:

5680

European-Non Finnish (NFE)

AF:

0.204

AC:

219990

AN:

1077320

Other (OTH)

AF:

0.213

AC:

12303

AN:

57870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

10451

20903

31354

41806

52257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7972

15944

23916

31888

39860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.243

AC:

36979

AN:

152126

Hom.:

4962

Cov.:

AF XY:

0.241

AC XY:

17919

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.360

AC:

14929

AN:

41474

American (AMR)

AF:

0.226

AC:

3461

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

810

AN:

3468

East Asian (EAS)

AF:

0.190

AC:

985

AN:

5178

South Asian (SAS)

AF:

0.139

AC:

669

AN:

4818

European-Finnish (FIN)

AF:

0.200

AC:

2119

AN:

10570

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13396

AN:

68006

Other (OTH)

AF:

0.219

AC:

463

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1433

2866

4298

5731

7164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.214

Hom.:

9542

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

LINK: link

Submissions by phenotype

not specified

Benign:2

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Autosomal recessive nonsyndromic hearing loss 104

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

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

LIST_S2

Benign

0.79

.;T;.;T;T

MetaRNN

Benign

0.0037

T;T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

2.3

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

.;.;N;.;.

REVEL

Benign

0.20

Sift

Benign

0.41

.;.;T;.;.

Sift4G

Benign

0.36

.;T;T;.;.

Polyphen

0.13

B;B;B;.;.

Vest4

0.042, 0.047

MPC

0.35

ClinPred

0.0032

GERP RS

1.1

Varity_R

0.031

gMVP

0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over