6-24848144-C-G

Variant names:

• chr6-24848144-C-G
• rs35331811
• NM_001286445.3:c.1045G>C

Variant summary

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

The NM_001286445.3(RIPOR2):​c.1045G>C​(p.Val349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,054 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V349M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 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.1045G>C	p.Val349Leu	missense_variant	Exon 12 of 22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.1045G>C	p.Val349Leu	missense_variant	Exon 12 of 22		NM_001286445.3	ENSP00000494268.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461054 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111620

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	.;T;.;T;T;.;T;T;.;T;T;.;T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
PhyloP100		4.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	.;.;N;.;.;N;N;N;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.099	.;.;T;.;.;T;T;T;.;.;.;.;.
Sift4G	Benign	0.31	.;T;T;.;.;T;T;T;.;.;.;.;.
Polyphen		0.98	D;D;D;.;.;P;D;.;P;P;.;.;.
Vest4		0.70, 0.71, 0.65, 0.66, 0.65
MutPred		0.17		Gain of catalytic residue at V320 (P = 0.1233);Gain of catalytic residue at V320 (P = 0.1233);Gain of catalytic residue at V320 (P = 0.1233);Gain of catalytic residue at V320 (P = 0.1233);.;Gain of catalytic residue at V320 (P = 0.1233);.;Gain of catalytic residue at V320 (P = 0.1233);Gain of catalytic residue at V320 (P = 0.1233);Gain of catalytic residue at V320 (P = 0.1233);.;Gain of catalytic residue at V320 (P = 0.1233);Gain of catalytic residue at V320 (P = 0.1233);
MVP		0.78
MPC		0.72
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.47
Mutation Taster		=88/12	polymorphism

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: rs35331811; hg19: chr6-24848372;