rs9393587

Variant names:

• chr6-24809625-C-T
• rs9393587
• NM_001286445.3:c.3043+92G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001286445.3(RIPOR2):​c.3043+92G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 868,940 control chromosomes in the GnomAD database, including 299,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (44425 hom., cov: 31)
  • Exomes 𝑓: 0.84 (255288 hom.)
• Consequence: RIPOR2 NM_001286445.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.508
• Publications: 5 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):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 104

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 21

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000282804 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-24809625-C-T is Benign according to our data. Variant chr6-24809625-C-T is described in ClinVar as Benign. ClinVar VariationId is 1262708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286445.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	NM_001286445.3	MANE Select	c.3043+92G>A		intron	N/A	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.3106+92G>A		intron	N/A	NP_055537.2
	RIPOR2	NM_001346031.2		c.2956+92G>A		intron	N/A	NP_001332960.1	F5GX51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.3043+92G>A		intron	N/A	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.3106+92G>A		intron	N/A	ENSP00000259698.4	Q9Y4F9-1
	ENSG00000282804	ENST00000562221.1	TSL:5	c.82+92G>A		intron	N/A	ENSP00000455145.1	H3BP45

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113298 AN: 151904 Hom.: 44403 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.730

GnomAD4 exome AF: 0.841 AC: 602768 AN: 716918 Hom.: 255288 AF XY: 0.843 AC XY: 317749 AN XY: 376720

African (AFR) AF: 0.466 AC: 8438 AN: 18112

American (AMR) AF: 0.853 AC: 27808 AN: 32592

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 15833 AN: 19996

East Asian (EAS) AF: 0.881 AC: 28706 AN: 32568

South Asian (SAS) AF: 0.865 AC: 55256 AN: 63884

European-Finnish (FIN) AF: 0.916 AC: 42735 AN: 46670

Middle Eastern (MID) AF: 0.748 AC: 3205 AN: 4284

European-Non Finnish (NFE) AF: 0.846 AC: 392266 AN: 463414

Other (OTH) AF: 0.806 AC: 28521 AN: 35398

GnomAD4 genome AF: 0.746 AC: 113365 AN: 152022 Hom.: 44425 Cov.: 31 AF XY: 0.754 AC XY: 56042 AN XY: 74336

African (AFR) AF: 0.479 AC: 19836 AN: 41404

American (AMR) AF: 0.810 AC: 12369 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 2716 AN: 3468

East Asian (EAS) AF: 0.879 AC: 4546 AN: 5170

South Asian (SAS) AF: 0.863 AC: 4156 AN: 4814

European-Finnish (FIN) AF: 0.916 AC: 9686 AN: 10578

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57417 AN: 68006

Other (OTH) AF: 0.728 AC: 1537 AN: 2110

Alfa AF: 0.764 Hom.: 6945

Bravo AF: 0.724

Asia WGS AF: 0.831 AC: 2886 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.75
PhyloP100		-0.51
PromoterAI		-0.034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9393587; hg19: chr6-24809853;