rs143785002

Variant names:

• chr6-24842946-T-G
• rs143785002
• NM_001286445.3:c.1773A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001286445.3(RIPOR2):​c.1773A>C​(p.Leu591Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,525,798 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.17
• 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
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004411757).
• BP6: Variant 6-24842946-T-G is Benign according to our data. Variant chr6-24842946-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1773A>C	p.Leu591Phe	missense	Exon 13 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.1836A>C	p.Leu612Phe	missense	Exon 14 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.1686A>C	p.Leu562Phe	missense	Exon 13 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.1773A>C	p.Leu591Phe	missense	Exon 13 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.1836A>C	p.Leu612Phe	missense	Exon 14 of 23	ENSP00000259698.4	Q9Y4F9-1
	RIPOR2	ENST00000378023.8	TSL:1	c.1686A>C	p.Leu562Phe	missense	Exon 13 of 14	ENSP00000367262.4	Q9Y4F9-2

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152178 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00173 AC: 315 AN: 181940 AF XY: 0.00138

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000639

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.000725

GnomAD4 exome AF: 0.000700 AC: 961 AN: 1373502 Hom.: 3 Cov.: 32 AF XY: 0.000662 AC XY: 446 AN XY: 673820

African (AFR) AF: 0.0136 AC: 414 AN: 30456

American (AMR) AF: 0.00157 AC: 48 AN: 30582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20348

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38978

South Asian (SAS) AF: 0.000127 AC: 9 AN: 71034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50070

Middle Eastern (MID) AF: 0.00262 AC: 14 AN: 5340

European-Non Finnish (NFE) AF: 0.000377 AC: 404 AN: 1070234

Other (OTH) AF: 0.00126 AC: 71 AN: 56460

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152296 Hom.: 2 Cov.: 31 AF XY: 0.00365 AC XY: 272 AN XY: 74476

African (AFR) AF: 0.0122 AC: 506 AN: 41558

American (AMR) AF: 0.00216 AC: 33 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00193 Hom.: 6

Bravo AF: 0.00447

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0141 AC: 53

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.00161 AC: 194

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.058
Sift	Benign	0.49	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.31		Loss of disorder (P = 0.1734)
MVP		0.043
MPC		0.33
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.055
gMVP		0.11
Mutation Taster		=98/2	polymorphism

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: rs143785002; hg19: chr6-24843174; COSMIC: COSV107272445;