rs9393597

Variant names:

• chr6-24972880-A-G
• rs9393597
• NM_001286446.3:c.76+68971T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001286446.3(RIPOR2):​c.76+68971T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,210 control chromosomes in the GnomAD database, including 2,494 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2494 hom., cov: 32)
• Consequence: RIPOR2 NM_001286446.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440
• Publications: 4 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

ENSG00000288887 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286446.3	c.76+68971T>C		intron_variant	Intron 1 of 13		NP_001273375.1
RIPOR2	XM_011515012.2	c.76+68971T>C		intron_variant	Intron 1 of 22		XP_011513314.1
RIPOR2	XM_006715275.3	c.76+68971T>C		intron_variant	Intron 1 of 21		XP_006715338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000510784.8	c.76+68971T>C		intron_variant	Intron 1 of 13	2		ENSP00000441305.1
ENSG00000288887	ENST00000716086.1	n.171+36644A>G		intron_variant	Intron 1 of 5
ENSG00000288887	ENST00000761913.1	n.180-3467A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23388 AN: 152094 Hom.: 2497 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.154 AC: 23381 AN: 152210 Hom.: 2494 Cov.: 32 AF XY: 0.162 AC XY: 12052 AN XY: 74418

African (AFR) AF: 0.0558 AC: 2318 AN: 41540

American (AMR) AF: 0.246 AC: 3760 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 636 AN: 3468

East Asian (EAS) AF: 0.471 AC: 2431 AN: 5164

South Asian (SAS) AF: 0.254 AC: 1228 AN: 4830

European-Finnish (FIN) AF: 0.186 AC: 1966 AN: 10578

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10417 AN: 68014

Other (OTH) AF: 0.181 AC: 382 AN: 2116

Alfa AF: 0.156 Hom.: 1636

Bravo AF: 0.155

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		-0.044
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9393597; hg19: chr6-24973108;