6-24848144-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001286445.3(RIPOR2):c.1045G>A(p.Val349Met) variant causes a missense change. The variant allele was found at a frequency of 0.00901 in 1,613,324 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 117 hom. )

Consequence

RIPOR2
NM_001286445.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.74

Publications

10 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=0.0045339167).

BP6

Variant 6-24848144-C-T is Benign according to our data. Variant chr6-24848144-C-T is described in ClinVar as Benign. ClinVar VariationId is 508603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00925 (1409/152280) while in subpopulation AMR AF = 0.0347 (531/15286). AF 95% confidence interval is 0.0323. There are 13 homozygotes in GnomAd4. There are 727 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3 link	c.1045G>A	p.Val349Met	missense_variant	Exon 12 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.1045G>A	p.Val349Met	missense_variant	Exon 12 of 22		NM_001286445.3	ENSP00000494268.2		A0A2R8YEE0

Frequencies

GnomAD3 genomes

AF:

0.00925

AC:

1408

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0165

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00683

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.0131

AC:

3242

AN:

247722

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.00151

Gnomad AMR exome

AF:

0.0464

Gnomad ASJ exome

AF:

0.000600

Gnomad EAS exome

AF:

0.0178

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.00677

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.00899

AC:

13134

AN:

1461044

Hom.:

117

Cov.:

AF XY:

0.00872

AC XY:

6337

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

33452

American (AMR)

AF:

0.0434

AC:

1938

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.000958

AC:

AN:

26104

East Asian (EAS)

AF:

0.0177

AC:

701

AN:

39654

South Asian (SAS)

AF:

0.00430

AC:

370

AN:

86104

European-Finnish (FIN)

AF:

0.0150

AC:

803

AN:

53376

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00797

AC:

8863

AN:

1111618

Other (OTH)

AF:

0.00633

AC:

382

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

651

1302

1952

2603

3254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.00925

AC:

1409

AN:

152280

Hom.:

Cov.:

AF XY:

0.00976

AC XY:

727

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41542

American (AMR)

AF:

0.0347

AC:

531

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.0166

AC:

AN:

5190

South Asian (SAS)

AF:

0.00476

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00684

AC:

465

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00787

Hom.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000755

AC:

ESP6500EA

AF:

0.00742

AC:

ExAC

AF:

0.0110

AC:

1326

Asia WGS

AF:

0.00808

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.Val320Met in exon 12 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 5.24% (567/10816) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35331811). -

Oct 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 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2018

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

0.097

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;D;.;D;D;.;D;D;.;D;D;.;D

MetaRNN

Benign

0.0045

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

MetaSVM

Uncertain

-0.18

PhyloP100

4.7

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.65

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

REVEL

Benign

0.29

Sift

Benign

0.042

.;.;D;.;.;D;D;D;.;.;.;.;.

Sift4G

Benign

0.097

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

Polyphen

1.0

D;D;D;.;.;D;D;.;D;D;.;.;.

Vest4

0.34, 0.38, 0.54, 0.55, 0.56

MPC

0.99

ClinPred

0.011

GERP RS

5.5

Varity_R

0.070

gMVP

0.51

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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