chr6-24809708-A-T

Variant names:

• chr6-24809708-A-T
• rs9379693
• NM_001286445.3:c.3043+9T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.3043+9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,517,870 control chromosomes in the GnomAD database, including 15,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1314 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14156 hom.)
• Consequence: RIPOR2 NM_001286445.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.338
• Publications: 9 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)

ENSG00000282804 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 6-24809708-A-T is Benign according to our data. Variant chr6-24809708-A-T is described in ClinVar as Benign. ClinVar VariationId is 517553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 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.3043+9T>A		intron	N/A	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.3106+9T>A		intron	N/A	NP_055537.2
	RIPOR2	NM_001346031.2		c.2956+9T>A		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.3043+9T>A		intron	N/A	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.3106+9T>A		intron	N/A	ENSP00000259698.4	Q9Y4F9-1
	ENSG00000282804	ENST00000562221.1	TSL:5	c.82+9T>A		intron	N/A	ENSP00000455145.1	H3BP45

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18902 AN: 152104 Hom.: 1312 Cov.: 32

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.140 AC: 21907 AN: 156336 AF XY: 0.139

Gnomad AFR exome AF: 0.0746

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.142 AC: 193750 AN: 1365652 Hom.: 14156 Cov.: 25 AF XY: 0.141 AC XY: 95378 AN XY: 675634

African (AFR) AF: 0.0714 AC: 2213 AN: 31004

American (AMR) AF: 0.155 AC: 5536 AN: 35650

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4240 AN: 24996

East Asian (EAS) AF: 0.109 AC: 3876 AN: 35574

South Asian (SAS) AF: 0.123 AC: 9680 AN: 78630

European-Finnish (FIN) AF: 0.157 AC: 7753 AN: 49232

Middle Eastern (MID) AF: 0.135 AC: 758 AN: 5614

European-Non Finnish (NFE) AF: 0.145 AC: 151870 AN: 1048054

Other (OTH) AF: 0.138 AC: 7824 AN: 56898

GnomAD4 genome AF: 0.124 AC: 18911 AN: 152218 Hom.: 1314 Cov.: 32 AF XY: 0.125 AC XY: 9303 AN XY: 74410

African (AFR) AF: 0.0773 AC: 3211 AN: 41546

American (AMR) AF: 0.143 AC: 2185 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3470

East Asian (EAS) AF: 0.101 AC: 522 AN: 5182

South Asian (SAS) AF: 0.108 AC: 519 AN: 4826

European-Finnish (FIN) AF: 0.162 AC: 1711 AN: 10578

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9823 AN: 68018

Other (OTH) AF: 0.107 AC: 225 AN: 2110

Alfa AF: 0.140 Hom.: 539

Bravo AF: 0.124

Asia WGS AF: 0.0890 AC: 310 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 104 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.7
DANN	Benign	0.88
PhyloP100		0.34
PromoterAI		0.00090	Neutral
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: rs9379693; hg19: chr6-24809936; COSMIC: COSV52418580;