chr6-24843106-G-A

Variant names:

• chr6-24843106-G-A
• rs142889670
• NM_001286445.3:c.1613C>T

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.1613C>T​(p.Ser538Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,964 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (3 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.39
• Publications: 9 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030991137).
• BP6: Variant 6-24843106-G-A is Benign according to our data. Variant chr6-24843106-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR 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.1613C>T	p.Ser538Leu	missense	Exon 13 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.1676C>T	p.Ser559Leu	missense	Exon 14 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.1526C>T	p.Ser509Leu	missense	Exon 13 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.1613C>T	p.Ser538Leu	missense	Exon 13 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.1676C>T	p.Ser559Leu	missense	Exon 14 of 23	ENSP00000259698.4	Q9Y4F9-1
	RIPOR2	ENST00000378023.8	TSL:1	c.1526C>T	p.Ser509Leu	missense	Exon 13 of 14	ENSP00000367262.4	Q9Y4F9-2

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 570 AN: 152148 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00146 AC: 363 AN: 248878 AF XY: 0.00108

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000728 AC: 1064 AN: 1461698 Hom.: 3 Cov.: 32 AF XY: 0.000673 AC XY: 489 AN XY: 727134

African (AFR) AF: 0.0136 AC: 457 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000383 AC: 426 AN: 1111856

Other (OTH) AF: 0.00123 AC: 74 AN: 60374

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152266 Hom.: 2 Cov.: 31 AF XY: 0.00369 AC XY: 275 AN XY: 74452

African (AFR) AF: 0.0123 AC: 510 AN: 41532

American (AMR) AF: 0.00222 AC: 34 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68032

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.0164 Hom.: 2355

Bravo AF: 0.00452

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0137 AC: 55

ESP6500EA AF: 0.000478 AC: 4

ExAC AF: 0.00164 AC: 198

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.4
DANN	Benign	0.47
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.93	T
PhyloP100		1.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.049
Sift	Benign	0.65	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.047
MVP		0.043
MPC		0.27
ClinPred		0.0016	T
GERP RS		4.4
Varity_R		0.025
gMVP		0.14
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: rs142889670; hg19: chr6-24843334; COSMIC: COSV52423869;