6-24818599-T-C

Position:

• chr6-24818599-T-C

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.2895A>G​(p.Leu965=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,550,650 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (172 hom., cov: 30)
  • Exomes 𝑓: 0.013 (277 hom.)
• Consequence: RIPOR2 NM_001286445.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36

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=-0.77).
• BP6: Variant 6-24818599-T-C is Benign according to our data. Variant chr6-24818599-T-C is described in ClinVar as [Benign]. Clinvar id is 508155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.2895A>G	p.Leu965=	synonymous_variant	20/22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.2895A>G	p.Leu965=	synonymous_variant	20/22		NM_001286445.3	ENSP00000494268	A2
RIPOR2	ENST00000259698.9	c.2958A>G	p.Leu986=	synonymous_variant	21/23	1		ENSP00000259698	A2
RIPOR2	ENST00000613507.4	c.2958A>G	p.Leu986=	synonymous_variant	21/23	5		ENSP00000482957	A2
RIPOR2	ENST00000538035.6	c.2808A>G	p.Leu936=	synonymous_variant	20/22	2		ENSP00000441138	A2

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4846 AN: 152066 Hom.: 171 Cov.: 30

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00988

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0134 AC: 2102 AN: 157274 Hom.: 60 AF XY: 0.0120 AC XY: 994 AN XY: 83144

Gnomad AFR exome AF: 0.0886

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000220

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0129 AC: 17983 AN: 1398466 Hom.: 277 Cov.: 30 AF XY: 0.0122 AC XY: 8406 AN XY: 689772

Gnomad4 AFR exome AF: 0.0894

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000266

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0319 AC: 4860 AN: 152184 Hom.: 172 Cov.: 30 AF XY: 0.0310 AC XY: 2307 AN XY: 74406

Gnomad4 AFR AF: 0.0864

Gnomad4 AMR AF: 0.0258

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00988

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0192 Hom.: 36

Bravo AF: 0.0371

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Leu986Leu in exon 21 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 9.15% (203/2218) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs61733143). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.7
DANN	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs61733143; hg19: chr6-24818827;