chr6-24843512-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.1207G>A(p.Glu403Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,537,788 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 152 hom., cov: 31)

Exomes 𝑓: 0.013 ( 268 hom. )

Consequence

RIPOR2
NM_001286445.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.59

Publications

7 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=0.0020503998).

BP6

Variant 6-24843512-C-T is Benign according to our data. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24843512-C-T is described in CliVar as Benign. Clinvar id is 508151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3 link	c.1207G>A	p.Glu403Lys	missense_variant	Exon 13 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.1207G>A	p.Glu403Lys	missense_variant	Exon 13 of 22		NM_001286445.3	ENSP00000494268.2		A0A2R8YEE0

Frequencies

GnomAD3 genomes

AF:

0.0308

AC:

4680

AN:

152070

Hom.:

152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0825

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0257

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00991

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0147

AC:

2882

AN:

196682

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.0855

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.00972

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0127

AC:

17630

AN:

1385600

Hom.:

268

Cov.:

AF XY:

0.0121

AC XY:

8256

AN XY:

680648

show subpopulations

African (AFR)

AF:

0.0851

AC:

2621

AN:

30810

American (AMR)

AF:

0.0200

AC:

653

AN:

32706

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

560

AN:

21816

East Asian (EAS)

AF:

0.000129

AC:

AN:

38726

South Asian (SAS)

AF:

0.000238

AC:

AN:

75518

European-Finnish (FIN)

AF:

0.00290

AC:

148

AN:

51044

Middle Eastern (MID)

AF:

0.00482

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.0118

AC:

12677

AN:

1072746

Other (OTH)

AF:

0.0162

AC:

922

AN:

56842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

790

1579

2369

3158

3948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.0308

AC:

4683

AN:

152188

Hom.:

152

Cov.:

AF XY:

0.0299

AC XY:

2222

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0823

AC:

3414

AN:

41482

American (AMR)

AF:

0.0256

AC:

392

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00991

AC:

674

AN:

68014

Other (OTH)

AF:

0.0331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

220

439

659

878

1098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0169

Hom.:

208

Bravo

AF:

0.0359

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.0813

AC:

315

ESP6500EA

AF:

0.0117

AC:

ExAC

AF:

0.0143

AC:

1726

Asia WGS

AF:

0.00491

AC:

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

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.Glu424Lys in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 9.36% (834/8906) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs34016544). -

Aug 25, 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. -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2019

Athena Diagnostics

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

0.071

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0065

T;T;T;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.77

.;T;.;T;T;.;T;T;.;T;T;.;T

MetaRNN

Benign

0.0021

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

2.6

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.72

.;.;N;.;.;N;N;N;.;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.23

.;.;T;.;.;T;T;T;.;.;.;.;.

Sift4G

Benign

0.52

.;T;T;.;.;T;T;T;.;.;.;.;.

Polyphen

0.0010

B;B;B;.;.;P;P;.;P;P;.;.;.

Vest4

0.052, 0.069, 0.13, 0.13

MPC

0.34

ClinPred

0.014

GERP RS

3.9

Varity_R

0.040

gMVP

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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