chr6-24840758-G-A

Variant names:

• chr6-24840758-G-A
• rs75574668
• NM_001286445.3:c.1858-1486C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.1858-1486C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,535,374 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (99 hom.)
• Consequence: RIPOR2 NM_001286445.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.914
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 6-24840758-G-A is Benign according to our data. Variant chr6-24840758-G-A is described in ClinVar as Benign. ClinVar VariationId is 586405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	NM_001286445.3	MANE Select	c.1858-1486C>T		intron	N/A	NP_001273374.1
	RIPOR2	NM_001286446.3		c.1890C>T	p.Asp630Asp	synonymous	Exon 14 of 14	NP_001273375.1
	RIPOR2	NM_001286447.2		c.1788C>T	p.Asp596Asp	synonymous	Exon 14 of 14	NP_001273376.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.1858-1486C>T		intron	N/A	ENSP00000494268.2
	RIPOR2	ENST00000259698.9	TSL:1	c.1921-1486C>T		intron	N/A	ENSP00000259698.4
	RIPOR2	ENST00000378023.8	TSL:1	c.1771-1159C>T		intron	N/A	ENSP00000367262.4

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3312 AN: 152108 Hom.: 122 Cov.: 31

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00560 AC: 719 AN: 128374 AF XY: 0.00509

Gnomad AFR exome AF: 0.0697

Gnomad AMR exome AF: 0.00484

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.000288

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00256

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00424 AC: 5869 AN: 1383148 Hom.: 99 Cov.: 31 AF XY: 0.00394 AC XY: 2686 AN XY: 682496

African (AFR) AF: 0.0758 AC: 2393 AN: 31572

American (AMR) AF: 0.00504 AC: 180 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25178

East Asian (EAS) AF: 0.000196 AC: 7 AN: 35730

South Asian (SAS) AF: 0.00245 AC: 194 AN: 79228

European-Finnish (FIN) AF: 0.000986 AC: 33 AN: 33460

Middle Eastern (MID) AF: 0.00600 AC: 34 AN: 5662

European-Non Finnish (NFE) AF: 0.00244 AC: 2634 AN: 1078728

Other (OTH) AF: 0.00679 AC: 393 AN: 57890

GnomAD4 genome AF: 0.0218 AC: 3319 AN: 152226 Hom.: 124 Cov.: 31 AF XY: 0.0203 AC XY: 1514 AN XY: 74432

African (AFR) AF: 0.0720 AC: 2988 AN: 41506

American (AMR) AF: 0.00680 AC: 104 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68014

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0116 Hom.: 16

Bravo AF: 0.0246

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		0.91
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

Other links and lift over

dbSNP: rs75574668; hg19: chr6-24840986; COSMIC: COSV52418210; COSMIC: COSV52418210;