6-24843427-G-C

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.1292C>G(p.Ser431Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,318 control chromosomes in the GnomAD database, including 433 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 ( 150 hom., cov: 31)

Exomes 𝑓: 0.013 ( 283 hom. )

Consequence

RIPOR2
NM_001286445.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.98

Publications

6 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):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: STRONG Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 104
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
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=0.0018798709).

BP6

Variant 6-24843427-G-C is Benign according to our data. Variant chr6-24843427-G-C is described in ClinVar as Benign. ClinVar VariationId is 508152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286445.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPOR2	NM_001286445.3	MANE Select	c.1292C>G	p.Ser431Cys	missense	Exon 13 of 22	NP_001273374.1	A0A2R8YEE0
RIPOR2	NM_014722.5		c.1355C>G	p.Ser452Cys	missense	Exon 14 of 23	NP_055537.2
RIPOR2	NM_001346031.2		c.1205C>G	p.Ser402Cys	missense	Exon 13 of 22	NP_001332960.1	F5GX51

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPOR2	ENST00000643898.2	MANE Select	c.1292C>G	p.Ser431Cys	missense	Exon 13 of 22	ENSP00000494268.2	A0A2R8YEE0
RIPOR2	ENST00000259698.9	TSL:1	c.1355C>G	p.Ser452Cys	missense	Exon 14 of 23	ENSP00000259698.4	Q9Y4F9-1
RIPOR2	ENST00000378023.8	TSL:1	c.1205C>G	p.Ser402Cys	missense	Exon 13 of 14	ENSP00000367262.4	Q9Y4F9-2

Frequencies

GnomAD3 genomes

AF:

0.0307

AC:

4674

AN:

152146

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0825

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0248

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00991

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0137

AC:

3422

AN:

249016

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.0858

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.0248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00961

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0127

AC:

18576

AN:

1461054

Hom.:

283

Cov.:

AF XY:

0.0120

AC XY:

8728

AN XY:

726662

show subpopulations

African (AFR)

AF:

0.0852

AC:

2853

AN:

33470

American (AMR)

AF:

0.0191

AC:

853

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0258

AC:

675

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.000243

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00285

AC:

152

AN:

53400

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0117

AC:

13014

AN:

1111310

Other (OTH)

AF:

0.0162

AC:

980

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

912

1824

2735

3647

4559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

572

1144

1716

2288

2860

<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:

0.0307

AC:

4677

AN:

152264

Hom.:

150

Cov.:

AF XY:

0.0297

AC XY:

2215

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0824

AC:

3421

AN:

41536

American (AMR)

AF:

0.0248

AC:

379

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00991

AC:

674

AN:

68018

Other (OTH)

AF:

0.0331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

221

441

662

882

1103

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:

0.0106

Hom.:

Bravo

AF:

0.0358

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.0804

AC:

319

ESP6500EA

AF:

0.0116

AC:

ExAC

AF:

0.0144

AC:

1737

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.0120

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

Eigen

Benign

-0.014

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

PhyloP100

2.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

REVEL

Benign

0.10

Sift

Benign

0.071

Sift4G

Uncertain

0.038

Polyphen

0.65

Vest4

0.022

MPC

0.30

ClinPred

0.028

GERP RS

4.9

Varity_R

0.075

gMVP

0.44

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over