chr6-24818599-T-C

Variant names:

• chr6-24818599-T-C
• rs61733143
• NM_001286445.3:c.2895A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014722.5(RIPOR2):​c.2958A>G​(p.Leu986Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,550,650 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (172 hom., cov: 30)
  • Exomes 𝑓: 0.013 (277 hom.)
• Consequence: RIPOR2 NM_014722.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-24818599-T-C is Benign according to our data. Variant chr6-24818599-T-C is described in ClinVar as Benign. ClinVar VariationId is 508155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014722.5. 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.2895A>G	p.Leu965Leu	synonymous	Exon 20 of 22	NP_001273374.1
	RIPOR2	NM_014722.5		c.2958A>G	p.Leu986Leu	synonymous	Exon 21 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.2808A>G	p.Leu936Leu	synonymous	Exon 20 of 22	NP_001332960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.2895A>G	p.Leu965Leu	synonymous	Exon 20 of 22	ENSP00000494268.2
	RIPOR2	ENST00000259698.9	TSL:1	c.2958A>G	p.Leu986Leu	synonymous	Exon 21 of 23	ENSP00000259698.4
	RIPOR2	ENST00000613507.4	TSL:5	c.2958A>G	p.Leu986Leu	synonymous	Exon 21 of 23	ENSP00000482957.1

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4846 AN: 152066 Hom.: 171 Cov.: 30

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00988

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0134 AC: 2102 AN: 157274 AF XY: 0.0120

Gnomad AFR exome AF: 0.0886

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0129 AC: 17983 AN: 1398466 Hom.: 277 Cov.: 30 AF XY: 0.0122 AC XY: 8406 AN XY: 689772

African (AFR) AF: 0.0894 AC: 2821 AN: 31546

American (AMR) AF: 0.0197 AC: 704 AN: 35652

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 642 AN: 25146

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35728

South Asian (SAS) AF: 0.000266 AC: 21 AN: 79096

European-Finnish (FIN) AF: 0.00296 AC: 146 AN: 49310

Middle Eastern (MID) AF: 0.00492 AC: 28 AN: 5696

European-Non Finnish (NFE) AF: 0.0117 AC: 12649 AN: 1078276

Other (OTH) AF: 0.0167 AC: 971 AN: 58016

GnomAD4 genome AF: 0.0319 AC: 4860 AN: 152184 Hom.: 172 Cov.: 30 AF XY: 0.0310 AC XY: 2307 AN XY: 74406

African (AFR) AF: 0.0864 AC: 3587 AN: 41512

American (AMR) AF: 0.0258 AC: 394 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00988 AC: 672 AN: 68014

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0198 Hom.: 40

Bravo AF: 0.0371

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.7
DANN	Benign	0.72
PhyloP100		-1.4
Mutation Taster		=95/5	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: rs61733143; hg19: chr6-24818827;