6-24843427-G-C

Position:

• chr6-24843427-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.1292C>G​(p.Ser431Cys) 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 1,613,318 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (150 hom., cov: 31)
  • 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: 1.98

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018798709).
• BP6: Variant 6-24843427-G-C is Benign according to our data. Variant chr6-24843427-G-C is described in ClinVar as [Benign]. Clinvar id is 508152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.1292C>G	p.Ser431Cys	missense_variant	13/22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1292C>G	p.Ser431Cys	missense_variant	13/22		NM_001286445.3	ENSP00000494268.2

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4674 AN: 152146 Hom.: 150 Cov.: 31

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00991

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0137 AC: 3422 AN: 249016 Hom.: 100 AF XY: 0.0119 AC XY: 1611 AN XY: 135078

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 SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00961

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0127 AC: 18576 AN: 1461054 Hom.: 283 Cov.: 32 AF XY: 0.0120 AC XY: 8728 AN XY: 726662

Gnomad4 AFR exome AF: 0.0852

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00285

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0307 AC: 4677 AN: 152264 Hom.: 150 Cov.: 31 AF XY: 0.0297 AC XY: 2215 AN XY: 74462

Gnomad4 AFR AF: 0.0824

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00991

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0106 Hom.: 18

Bravo AF: 0.0358

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.0804 AC: 319

ESP6500EA AF: 0.0116 AC: 96

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Ser452Cys in exon 14 of FAM65B: This variant is not expected to have clinical significance because it has been identified in 8.66% (848/9796) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs34298086). -
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. -

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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	.;T;.;T;T;.;T;T;.;T;T;.;T
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	.;.;N;.;.;N;N;N;.;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.071	.;.;T;.;.;D;D;D;.;.;.;.;.
Sift4G	Uncertain	0.038	.;D;D;.;.;T;T;T;.;.;.;.;.
Polyphen		0.65	P;P;P;.;.;P;P;.;P;P;.;.;.
Vest4		0.022, 0.024, 0.082, 0.094
MPC		0.30
ClinPred		0.028	T
GERP RS		4.9
Varity_R		0.075
gMVP		0.44

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: rs34298086; hg19: chr6-24843655;