NM_001286445.3:c.2540G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001286445.3(RIPOR2):​c.2540G>C​(p.Arg847Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 33)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Not reported in ClinVar
• 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):

• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.2540G>C	p.Arg847Pro	missense_variant	Exon 18 of 22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.2540G>C	p.Arg847Pro	missense_variant	Exon 18 of 22		NM_001286445.3	ENSP00000494268.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;T;T;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D;.;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.41	T
PhyloP100		2.3
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.8	.;.;D;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.086	.;.;T;.;.
Sift4G	Uncertain	0.044	.;D;D;.;.
Polyphen		0.94	P;P;P;.;.
Vest4		0.50, 0.51
MutPred		0.50		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;.;
MVP		0.63
MPC		1.0
ClinPred		0.97	D
GERP RS		1.1
Varity_R		0.47
gMVP		0.73
Mutation Taster		=78/22	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: rs9461073; hg19: chr6-24828490;