rs74477879

Variant names:

• chr6-24847623-G-C
• rs74477879
• ENST00000259698.9:c.1146C>G

Variant summary

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

The NM_014722.5(RIPOR2):​c.1146C>G​(p.Phe382Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,551,674 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (95 hom.)
• Consequence: RIPOR2 NM_014722.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.74
• Publications: 3 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014749169).
• BP6: Variant 6-24847623-G-C is Benign according to our data. Variant chr6-24847623-G-C is described in ClinVar as Benign. ClinVar VariationId is 509125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	NM_001286445.3	MANE Select	c.1164+402C>G		intron	N/A	NP_001273374.1
	RIPOR2	NM_014722.5		c.1146C>G	p.Phe382Leu	missense	Exon 13 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.1077+402C>G		intron	N/A	NP_001332960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000259698.9	TSL:1	c.1146C>G	p.Phe382Leu	missense	Exon 13 of 23	ENSP00000259698.4
	RIPOR2	ENST00000643898.2	MANE Select	c.1164+402C>G		intron	N/A	ENSP00000494268.2
	RIPOR2	ENST00000378023.8	TSL:1	c.1077+402C>G		intron	N/A	ENSP00000367262.4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3254 AN: 152196 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00515 AC: 805 AN: 156436 AF XY: 0.00438

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000179

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00356 AC: 4980 AN: 1399360 Hom.: 95 Cov.: 31 AF XY: 0.00322 AC XY: 2223 AN XY: 690188

African (AFR) AF: 0.0756 AC: 2387 AN: 31592

American (AMR) AF: 0.00504 AC: 180 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79236

European-Finnish (FIN) AF: 0.000568 AC: 28 AN: 49266

Middle Eastern (MID) AF: 0.00579 AC: 33 AN: 5698

European-Non Finnish (NFE) AF: 0.00185 AC: 2000 AN: 1078926

Other (OTH) AF: 0.00586 AC: 340 AN: 58018

GnomAD4 genome AF: 0.0214 AC: 3261 AN: 152314 Hom.: 125 Cov.: 32 AF XY: 0.0198 AC XY: 1477 AN XY: 74476

African (AFR) AF: 0.0718 AC: 2983 AN: 41556

American (AMR) AF: 0.00699 AC: 107 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68030

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00464 Hom.: 12

Bravo AF: 0.0244

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.00724 AC: 188

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.00069	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.91	T
PhyloP100		2.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.035
Sift	Benign	0.70	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.081
MutPred		0.31		Loss of solvent accessibility (P = 0.001)
MVP		0.10
MPC		0.35
ClinPred		0.0087	T
GERP RS		4.3
Varity_R		0.089
gMVP		0.37
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74477879; hg19: chr6-24847851; COSMIC: COSV52419202; COSMIC: COSV52419202;