chr6-24843224-G-A

Variant names:

• chr6-24843224-G-A
• rs35780910
• NM_001286445.3:c.1495C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.1495C>T​(p.Arg499Cys) 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 1,613,968 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R499H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (151 hom., cov: 32)
  • Exomes 𝑓: 0.013 (283 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.28
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018260479).
• BP6: Variant 6-24843224-G-A is Benign according to our data. Variant chr6-24843224-G-A is described in ClinVar as Benign. ClinVar VariationId is 508153.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	c.1495C>T	p.Arg499Cys	missense_variant	Exon 13 of 22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1495C>T	p.Arg499Cys	missense_variant	Exon 13 of 22		NM_001286445.3	ENSP00000494268.2

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4671 AN: 152148 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0137 AC: 3419 AN: 248946 AF XY: 0.0119

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: 0.00959

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0127 AC: 18582 AN: 1461702 Hom.: 283 Cov.: 32 AF XY: 0.0120 AC XY: 8731 AN XY: 727136

African (AFR) AF: 0.0852 AC: 2854 AN: 33480

American (AMR) AF: 0.0191 AC: 853 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 675 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53398

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13018 AN: 1111866

Other (OTH) AF: 0.0162 AC: 981 AN: 60374

GnomAD4 genome AF: 0.0307 AC: 4674 AN: 152266 Hom.: 151 Cov.: 32 AF XY: 0.0297 AC XY: 2215 AN XY: 74460

African (AFR) AF: 0.0823 AC: 3418 AN: 41528

American (AMR) AF: 0.0248 AC: 379 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00992 AC: 675 AN: 68022

Other (OTH) AF: 0.0327 AC: 69 AN: 2112

Alfa AF: 0.0179 Hom.: 143

Bravo AF: 0.0359

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.0810 AC: 309

ESP6500EA AF: 0.0114 AC: 94

ExAC AF: 0.0144 AC: 1737

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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.Arg520Cys in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 8.65% (848/9800) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs35780910). -

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	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.0028	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;.;D;D;.;D;D;.;D;D;.;D
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.51	.;.;N;.;.;N;N;N;.;.;.;.;.
REVEL	Benign	0.061
Sift	Uncertain	0.020	.;.;D;.;.;D;D;D;.;.;.;.;.
Sift4G	Uncertain	0.052	.;T;T;.;.;T;T;T;.;.;.;.;.
Polyphen		0.0020	B;B;B;.;.;D;B;.;D;D;.;.;.
Vest4		0.12, 0.14, 0.25, 0.24, 0.24
MPC		0.92
ClinPred		0.023	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35780910; hg19: chr6-24843452;