rs4256430

Variant names:

• chr6-24862847-G-A
• rs4256430
• NM_001286445.3:c.652-1811C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001286445.3(RIPOR2):​c.652-1811C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 150,764 control chromosomes in the GnomAD database, including 13,603 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (13603 hom., cov: 28)
• Consequence: RIPOR2 NM_001286445.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.446 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.652-1811C>T		intron	N/A	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.565-1811C>T		intron	N/A	NP_055537.2
	RIPOR2	NM_001346031.2		c.565-1811C>T		intron	N/A	NP_001332960.1	F5GX51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.652-1811C>T		intron	N/A	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.565-1811C>T		intron	N/A	ENSP00000259698.4	Q9Y4F9-1
	RIPOR2	ENST00000378023.8	TSL:1	c.565-1811C>T		intron	N/A	ENSP00000367262.4	Q9Y4F9-2

Frequencies

GnomAD3 genomes AF: 0.422 AC: 63608 AN: 150648 Hom.: 13602 Cov.: 28

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.453

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.422 AC: 63637 AN: 150764 Hom.: 13603 Cov.: 28 AF XY: 0.416 AC XY: 30586 AN XY: 73552

African (AFR) AF: 0.425 AC: 17431 AN: 40988

American (AMR) AF: 0.388 AC: 5880 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1746 AN: 3470

East Asian (EAS) AF: 0.317 AC: 1612 AN: 5088

South Asian (SAS) AF: 0.378 AC: 1804 AN: 4770

European-Finnish (FIN) AF: 0.318 AC: 3276 AN: 10294

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.450 AC: 30477 AN: 67712

Other (OTH) AF: 0.446 AC: 934 AN: 2092

Alfa AF: 0.442 Hom.: 30465

Bravo AF: 0.430

Asia WGS AF: 0.344 AC: 1199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.56
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4256430;

hg19: chr6-24863075;