NM_001286445.3:c.2937T>C

Variant names:

• chr6-24818557-A-G
• rs9358802
• NM_001286445.3:c.2937T>C

Variant summary

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

The NM_001286445.3(RIPOR2):​c.2937T>C​(p.Ala979Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,547,186 control chromosomes in the GnomAD database, including 89,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8023 hom., cov: 30)
  • Exomes 𝑓: 0.33 (81318 hom.)
• Consequence: RIPOR2 NM_001286445.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0730
• 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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 6-24818557-A-G is Benign according to our data. Variant chr6-24818557-A-G is described in ClinVar as Benign. ClinVar VariationId is 508096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 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.2937T>C	p.Ala979Ala	synonymous	Exon 20 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.3000T>C	p.Ala1000Ala	synonymous	Exon 21 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.2850T>C	p.Ala950Ala	synonymous	Exon 20 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.2937T>C	p.Ala979Ala	synonymous	Exon 20 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.3000T>C	p.Ala1000Ala	synonymous	Exon 21 of 23	ENSP00000259698.4	Q9Y4F9-1
	RIPOR2	ENST00000613507.4	TSL:5	c.3000T>C	p.Ala1000Ala	synonymous	Exon 21 of 23	ENSP00000482957.1	Q9Y4F9-1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46460 AN: 151866 Hom.: 8017 Cov.: 30

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.378 AC: 59163 AN: 156506 AF XY: 0.379

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.686

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.332 AC: 463697 AN: 1395202 Hom.: 81318 Cov.: 31 AF XY: 0.336 AC XY: 231096 AN XY: 688286

African (AFR) AF: 0.179 AC: 5660 AN: 31544

American (AMR) AF: 0.440 AC: 15649 AN: 35600

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6549 AN: 25088

East Asian (EAS) AF: 0.664 AC: 23705 AN: 35690

South Asian (SAS) AF: 0.448 AC: 35266 AN: 78758

European-Finnish (FIN) AF: 0.396 AC: 19491 AN: 49210

Middle Eastern (MID) AF: 0.251 AC: 1421 AN: 5658

European-Non Finnish (NFE) AF: 0.313 AC: 336464 AN: 1075844

Other (OTH) AF: 0.337 AC: 19492 AN: 57810

GnomAD4 genome AF: 0.306 AC: 46500 AN: 151984 Hom.: 8023 Cov.: 30 AF XY: 0.315 AC XY: 23385 AN XY: 74256

African (AFR) AF: 0.187 AC: 7763 AN: 41496

American (AMR) AF: 0.375 AC: 5731 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3496 AN: 5116

South Asian (SAS) AF: 0.459 AC: 2207 AN: 4808

European-Finnish (FIN) AF: 0.392 AC: 4142 AN: 10554

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21105 AN: 67956

Other (OTH) AF: 0.314 AC: 662 AN: 2110

Alfa AF: 0.292 Hom.: 2928

Bravo AF: 0.300

Asia WGS AF: 0.542 AC: 1881 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.8
DANN	Benign	0.59
PhyloP100		-0.073
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: rs9358802; hg19: chr6-24818785; COSMIC: COSV52418661;