rs35698586

Variant names:

• chr6-24848103-T-C
• rs35698586
• NM_001286445.3:c.1086A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001286445.3(RIPOR2):​c.1086A>G​(p.Ala362Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,613,958 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (99 hom.)
• Consequence: RIPOR2 NM_001286445.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.67

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-24848103-T-C is Benign according to our data. Variant chr6-24848103-T-C is described in ClinVar as [Benign]. Clinvar id is 509124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.1086A>G	p.Ala362Ala	synonymous_variant	Exon 12 of 22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1086A>G	p.Ala362Ala	synonymous_variant	Exon 12 of 22		NM_001286445.3	ENSP00000494268.2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3245 AN: 152232 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00595 AC: 1482 AN: 248936 Hom.: 30 AF XY: 0.00485 AC XY: 655 AN XY: 135070

Gnomad AFR exome AF: 0.0718

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00356 AC: 5199 AN: 1461608 Hom.: 99 Cov.: 31 AF XY: 0.00320 AC XY: 2328 AN XY: 727088

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.0213 AC: 3252 AN: 152350 Hom.: 124 Cov.: 32 AF XY: 0.0198 AC XY: 1477 AN XY: 74522

Gnomad4 AFR AF: 0.0715

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00195

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0104 Hom.: 30

Bravo AF: 0.0243

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00119

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.Ala333Ala in exon 12 of FAM65B: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 7.47% (707/9468) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs35698586). -

Oct 23, 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 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 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
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.54
DANN	Benign	0.53

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

LitVar

Other links and lift over

dbSNP: rs35698586; hg19: chr6-24848331;