6-24806047-T-C

Variant names:

• chr6-24806047-T-C
• rs113707390
• NM_001286445.3:c.*326A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001286445.3(RIPOR2):​c.*326A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 245,256 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: RIPOR2 NM_001286445.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.547
• Publications: 2 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

ENSG00000282804 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-24806047-T-C is Benign according to our data. Variant chr6-24806047-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1316858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1642/152220) while in subpopulation AFR AF = 0.0312 (1295/41528). AF 95% confidence interval is 0.0298. There are 17 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPOR2	NM_001286445.3	c.*326A>G		3_prime_UTR_variant	Exon 22 of 22	ENST00000643898.2	NP_001273374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPOR2	ENST00000643898.2	c.*326A>G		3_prime_UTR_variant	Exon 22 of 22		NM_001286445.3	ENSP00000494268.2
ENSG00000282804	ENST00000562221.1	c.*6+320A>G		intron_variant	Intron 2 of 2	5		ENSP00000455145.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1623 AN: 152102 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.00259 AC: 241 AN: 93036 Hom.: 0 Cov.: 0 AF XY: 0.00249 AC XY: 120 AN XY: 48118

African (AFR) AF: 0.0200 AC: 44 AN: 2200

American (AMR) AF: 0.00518 AC: 9 AN: 1738

Ashkenazi Jewish (ASJ) AF: 0.00224 AC: 7 AN: 3126

East Asian (EAS) AF: 0.000247 AC: 1 AN: 4048

South Asian (SAS) AF: 0.00254 AC: 26 AN: 10230

European-Finnish (FIN) AF: 0.000965 AC: 5 AN: 5184

Middle Eastern (MID) AF: 0.0191 AC: 9 AN: 470

European-Non Finnish (NFE) AF: 0.00196 AC: 117 AN: 59846

Other (OTH) AF: 0.00371 AC: 23 AN: 6194

GnomAD4 genome AF: 0.0108 AC: 1642 AN: 152220 Hom.: 17 Cov.: 32 AF XY: 0.0107 AC XY: 800 AN XY: 74422

African (AFR) AF: 0.0312 AC: 1295 AN: 41528

American (AMR) AF: 0.00798 AC: 122 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5168

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68012

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00770 Hom.: 0

Bravo AF: 0.0124

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.6
DANN	Benign	0.82
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism

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: rs113707390; hg19: chr6-24806275;