rs9461073

Variant names:

• chr6-24828262-C-T
• rs9461073
• NM_001286445.3:c.2540G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24828262-C-T
• chr6-24828262-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.2540G>A​(p.Arg847Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,548,872 control chromosomes in the GnomAD database, including 35,327 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R847W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (4962 hom., cov: 33)
  • Exomes 𝑓: 0.21 (30365 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.32
• Publications: 20 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
• 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
• autosomal recessive nonsyndromic hearing loss 104

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037442148).
• BP6: Variant 6-24828262-C-T is Benign according to our data. Variant chr6-24828262-C-T is described in ClinVar as Benign. ClinVar VariationId is 508154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 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.2540G>A	p.Arg847Gln	missense	Exon 18 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.2603G>A	p.Arg868Gln	missense	Exon 19 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.2453G>A	p.Arg818Gln	missense	Exon 18 of 22	NP_001332960.1	F5GX51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.2540G>A	p.Arg847Gln	missense	Exon 18 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.2603G>A	p.Arg868Gln	missense	Exon 19 of 23	ENSP00000259698.4	Q9Y4F9-1
	RIPOR2	ENST00000613507.4	TSL:5	c.2603G>A	p.Arg868Gln	missense	Exon 19 of 23	ENSP00000482957.1	Q9Y4F9-1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36911 AN: 152008 Hom.: 4946 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.201 AC: 31027 AN: 154490 AF XY: 0.196

Gnomad AFR exome AF: 0.357

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.205 AC: 286733 AN: 1396746 Hom.: 30365 Cov.: 33 AF XY: 0.202 AC XY: 139449 AN XY: 688872

African (AFR) AF: 0.364 AC: 11460 AN: 31444

American (AMR) AF: 0.217 AC: 7720 AN: 35526

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5740 AN: 25124

East Asian (EAS) AF: 0.207 AC: 7355 AN: 35610

South Asian (SAS) AF: 0.147 AC: 11623 AN: 78986

European-Finnish (FIN) AF: 0.192 AC: 9454 AN: 49186

Middle Eastern (MID) AF: 0.192 AC: 1088 AN: 5680

European-Non Finnish (NFE) AF: 0.204 AC: 219990 AN: 1077320

Other (OTH) AF: 0.213 AC: 12303 AN: 57870

GnomAD4 genome AF: 0.243 AC: 36979 AN: 152126 Hom.: 4962 Cov.: 33 AF XY: 0.241 AC XY: 17919 AN XY: 74380

African (AFR) AF: 0.360 AC: 14929 AN: 41474

American (AMR) AF: 0.226 AC: 3461 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 810 AN: 3468

East Asian (EAS) AF: 0.190 AC: 985 AN: 5178

South Asian (SAS) AF: 0.139 AC: 669 AN: 4818

European-Finnish (FIN) AF: 0.200 AC: 2119 AN: 10570

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13396 AN: 68006

Other (OTH) AF: 0.219 AC: 463 AN: 2114

Alfa AF: 0.214 Hom.: 9542

Bravo AF: 0.256

TwinsUK AF: 0.214 AC: 792

ALSPAC AF: 0.219 AC: 843

ESP6500AA AF: 0.346 AC: 479

ESP6500EA AF: 0.195 AC: 621

ExAC AF: 0.178 AC: 4480

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 104 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Benign	0.41	T
Sift4G	Benign	0.36	T
Polyphen		0.13	B
Vest4		0.042
MPC		0.35
ClinPred		0.0032	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9461073; hg19: chr6-24828490; COSMIC: COSV52418594;