NM_001286445.3:c.1207G>A

Variant names:

• chr6-24843512-C-T
• rs34016544
• NM_001286445.3:c.1207G>A

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.59
• 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=0.0020503998).
• 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	c.1207G>A	p.Glu403Lys	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.1207G>A	p.Glu403Lys	missense_variant	Exon 13 of 22		NM_001286445.3	ENSP00000494268.2

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4680 AN: 152070 Hom.: 152 Cov.: 31

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

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.: 32 AF XY: 0.0121 AC XY: 8256 AN XY: 680648

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: 5 AN: 38726

South Asian (SAS) AF: 0.000238 AC: 18 AN: 75518

European-Finnish (FIN) AF: 0.00290 AC: 148 AN: 51044

Middle Eastern (MID) AF: 0.00482 AC: 26 AN: 5392

European-Non Finnish (NFE) AF: 0.0118 AC: 12677 AN: 1072746

Other (OTH) AF: 0.0162 AC: 922 AN: 56842

GnomAD4 genome AF: 0.0308 AC: 4683 AN: 152188 Hom.: 152 Cov.: 31 AF XY: 0.0299 AC XY: 2222 AN XY: 74418

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: 97 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00991 AC: 674 AN: 68014

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0169 Hom.: 208

Bravo AF: 0.0359

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.0813 AC: 315

ESP6500EA AF: 0.0117 AC: 97

ExAC AF: 0.0143 AC: 1726

Asia WGS AF: 0.00491 AC: 18 AN: 3478

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.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	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
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	N
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	T
PhyloP100		2.6
PrimateAI	Benign	0.28	T
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	T
GERP RS		3.9
Varity_R		0.040
gMVP		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34016544; hg19: chr6-24843740;