6-24806366-C-T

Variant names:

• chr6-24806366-C-T
• rs9358799
• NM_001286445.3:c.*7G>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.*7G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,524,680 control chromosomes in the GnomAD database, including 200,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16113 hom., cov: 32)
  • Exomes 𝑓: 0.51 (184296 hom.)
• Consequence: RIPOR2 NM_001286445.3 3_prime_UTR
• Scores: Splicing: ADA: 0.01401
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.390
• Publications: 17 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=-0.65).
• BP6: Variant 6-24806366-C-T is Benign according to our data. Variant chr6-24806366-C-T is described in ClinVar as Benign. ClinVar VariationId is 517548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.531 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.*7G>A		3_prime_UTR	Exon 22 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.*7G>A		3_prime_UTR	Exon 23 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.*7G>A		3_prime_UTR	Exon 22 of 22	NP_001332960.1	F5GX51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.*7G>A		3_prime_UTR	Exon 22 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.*7G>A		3_prime_UTR	Exon 23 of 23	ENSP00000259698.4	Q9Y4F9-1
	ENSG00000282804	ENST00000562221.1	TSL:5	c.*6+1G>A		splice_donor intron	N/A	ENSP00000455145.1	H3BP45

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67887 AN: 151832 Hom.: 16113 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.427

GnomAD2 exomes AF: 0.465 AC: 72494 AN: 155784 AF XY: 0.469

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.414

Gnomad ASJ exome AF: 0.534

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.512 AC: 703348 AN: 1372730 Hom.: 184296 Cov.: 24 AF XY: 0.512 AC XY: 347178 AN XY: 678548

African (AFR) AF: 0.299 AC: 9314 AN: 31112

American (AMR) AF: 0.421 AC: 14949 AN: 35492

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 13254 AN: 24974

East Asian (EAS) AF: 0.215 AC: 7675 AN: 35640

South Asian (SAS) AF: 0.432 AC: 33977 AN: 78578

European-Finnish (FIN) AF: 0.520 AC: 25611 AN: 49230

Middle Eastern (MID) AF: 0.516 AC: 2921 AN: 5664

European-Non Finnish (NFE) AF: 0.539 AC: 568351 AN: 1054966

Other (OTH) AF: 0.478 AC: 27296 AN: 57074

GnomAD4 genome AF: 0.447 AC: 67923 AN: 151950 Hom.: 16113 Cov.: 32 AF XY: 0.446 AC XY: 33136 AN XY: 74264

African (AFR) AF: 0.311 AC: 12891 AN: 41442

American (AMR) AF: 0.441 AC: 6736 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1848 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1033 AN: 5172

South Asian (SAS) AF: 0.420 AC: 2025 AN: 4826

European-Finnish (FIN) AF: 0.522 AC: 5498 AN: 10530

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36405 AN: 67946

Other (OTH) AF: 0.422 AC: 889 AN: 2108

Alfa AF: 0.492 Hom.: 32699

Bravo AF: 0.433

Asia WGS AF: 0.298 AC: 1037 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9358799; hg19: chr6-24806594; COSMIC: COSV52418565;