6-24809646-A-C

Variant names:

• chr6-24809646-A-C
• rs55640933
• NM_001286445.3:c.3043+71T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001286445.3(RIPOR2):​c.3043+71T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,021,250 control chromosomes in the GnomAD database, including 59,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (8101 hom., cov: 31)
  • Exomes 𝑓: 0.34 (51330 hom.)
• Consequence: RIPOR2 NM_001286445.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.320
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-24809646-A-C is Benign according to our data. Variant chr6-24809646-A-C is described in ClinVar as Benign. ClinVar VariationId is 1228095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 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.3043+71T>G		intron	N/A	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.3106+71T>G		intron	N/A	NP_055537.2
	RIPOR2	NM_001346031.2		c.2956+71T>G		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.3043+71T>G		intron	N/A	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.3106+71T>G		intron	N/A	ENSP00000259698.4	Q9Y4F9-1
	ENSG00000282804	ENST00000562221.1	TSL:5	c.82+71T>G		intron	N/A	ENSP00000455145.1	H3BP45

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46894 AN: 151774 Hom.: 8092 Cov.: 31

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.340 AC: 295181 AN: 869358 Hom.: 51330 AF XY: 0.344 AC XY: 154237 AN XY: 448922

African (AFR) AF: 0.193 AC: 4102 AN: 21214

American (AMR) AF: 0.438 AC: 15079 AN: 34414

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 5659 AN: 21716

East Asian (EAS) AF: 0.659 AC: 21835 AN: 33138

South Asian (SAS) AF: 0.445 AC: 30327 AN: 68096

European-Finnish (FIN) AF: 0.396 AC: 19175 AN: 48420

Middle Eastern (MID) AF: 0.250 AC: 1167 AN: 4672

European-Non Finnish (NFE) AF: 0.309 AC: 184353 AN: 597374

Other (OTH) AF: 0.334 AC: 13484 AN: 40314

GnomAD4 genome AF: 0.309 AC: 46942 AN: 151892 Hom.: 8101 Cov.: 31 AF XY: 0.318 AC XY: 23598 AN XY: 74222

African (AFR) AF: 0.198 AC: 8210 AN: 41416

American (AMR) AF: 0.376 AC: 5733 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3464

East Asian (EAS) AF: 0.677 AC: 3486 AN: 5148

South Asian (SAS) AF: 0.457 AC: 2190 AN: 4796

European-Finnish (FIN) AF: 0.394 AC: 4152 AN: 10546

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21115 AN: 67956

Other (OTH) AF: 0.316 AC: 667 AN: 2108

Alfa AF: 0.300 Hom.: 925

Bravo AF: 0.304

Asia WGS AF: 0.546 AC: 1894 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.9
DANN	Benign	0.56
PhyloP100		-0.32
PromoterAI		0.0011	Neutral
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: rs55640933; hg19: chr6-24809874; COSMIC: COSV52418652;