rs115680381

Variant names:

• chr6-24806485-A-G
• rs115680381
• NM_001286445.3:c.3044-12T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001286445.3(RIPOR2):​c.3044-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,522,738 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (49 hom.)
• Consequence: RIPOR2 NM_001286445.3 intron
• Scores: Splicing: ADA: 0.00008783
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.94
• Publications: 0 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
• autosomal recessive nonsyndromic hearing loss 104

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000282804 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-24806485-A-G is Benign according to our data. Variant chr6-24806485-A-G is described in ClinVar as Benign. ClinVar VariationId is 517552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.3044-12T>C		intron	N/A	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.3107-12T>C		intron	N/A	NP_055537.2
	RIPOR2	NM_001346031.2		c.2957-12T>C		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.3044-12T>C		intron	N/A	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.3107-12T>C		intron	N/A	ENSP00000259698.4	Q9Y4F9-1
	ENSG00000282804	ENST00000562221.1	TSL:5	c.83-12T>C		intron	N/A	ENSP00000455145.1	H3BP45

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 895 AN: 149392 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.0856

Gnomad AMR AF: 0.00428

Gnomad ASJ AF: 0.00407

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.00758

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00884

Gnomad OTH AF: 0.00398

GnomAD2 exomes AF: 0.00559 AC: 772 AN: 138184 AF XY: 0.00568

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00292

Gnomad EAS exome AF: 0.000100

Gnomad FIN exome AF: 0.00682

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00770 AC: 10571 AN: 1373228 Hom.: 49 Cov.: 25 AF XY: 0.00738 AC XY: 5009 AN XY: 678280

African (AFR) AF: 0.00111 AC: 34 AN: 30720

American (AMR) AF: 0.00215 AC: 72 AN: 33560

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 83 AN: 24926

East Asian (EAS) AF: 0.0000567 AC: 2 AN: 35278

South Asian (SAS) AF: 0.00193 AC: 149 AN: 77302

European-Finnish (FIN) AF: 0.00913 AC: 450 AN: 49264

Middle Eastern (MID) AF: 0.00265 AC: 15 AN: 5650

European-Non Finnish (NFE) AF: 0.00886 AC: 9389 AN: 1059364

Other (OTH) AF: 0.00660 AC: 377 AN: 57164

GnomAD4 genome AF: 0.00598 AC: 894 AN: 149510 Hom.: 7 Cov.: 33 AF XY: 0.00558 AC XY: 407 AN XY: 72884

African (AFR) AF: 0.00144 AC: 59 AN: 41006

American (AMR) AF: 0.00427 AC: 63 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.00407 AC: 14 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00107 AC: 5 AN: 4674

European-Finnish (FIN) AF: 0.00758 AC: 77 AN: 10158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00882 AC: 592 AN: 67100

Other (OTH) AF: 0.00393 AC: 8 AN: 2034

Alfa AF: 0.00664 Hom.: 0

Bravo AF: 0.00584

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.6
DANN	Benign	0.47
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.14		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: rs115680381; hg19: chr6-24806713;