rs35254980

Variant names:

• chr6-24848117-C-A
• rs35254980
• NM_001286445.3:c.1072G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-24848117-C-A
• chr6-24848117-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286445.3(RIPOR2):​c.1072G>T​(p.Ala358Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,613,742 control chromosomes in the GnomAD database, including 222 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A358T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (123 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (99 hom.)
• Consequence: RIPOR2 NM_001286445.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.994
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013438761).
• BP6: Variant 6-24848117-C-A is Benign according to our data. Variant chr6-24848117-C-A is described in ClinVar as Benign. ClinVar VariationId is 509123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0692 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.1072G>T	p.Ala358Ser	missense	Exon 12 of 22	NP_001273374.1	A0A2R8YEE0
	RIPOR2	NM_014722.5		c.985G>T	p.Ala329Ser	missense	Exon 12 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.985G>T	p.Ala329Ser	missense	Exon 12 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.1072G>T	p.Ala358Ser	missense	Exon 12 of 22	ENSP00000494268.2	A0A2R8YEE0
	RIPOR2	ENST00000259698.9	TSL:1	c.985G>T	p.Ala329Ser	missense	Exon 12 of 23	ENSP00000259698.4	Q9Y4F9-1
	RIPOR2	ENST00000378023.8	TSL:1	c.985G>T	p.Ala329Ser	missense	Exon 12 of 14	ENSP00000367262.4	Q9Y4F9-2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3235 AN: 152168 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0714

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00593 AC: 1474 AN: 248672 AF XY: 0.00484

Gnomad AFR exome AF: 0.0713

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00356 AC: 5198 AN: 1461456 Hom.: 99 Cov.: 31 AF XY: 0.00321 AC XY: 2331 AN XY: 726988

African (AFR) AF: 0.0752 AC: 2516 AN: 33470

American (AMR) AF: 0.00481 AC: 215 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86200

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53392

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5766

European-Non Finnish (NFE) AF: 0.00183 AC: 2039 AN: 1111774

Other (OTH) AF: 0.00572 AC: 345 AN: 60364

GnomAD4 genome AF: 0.0213 AC: 3242 AN: 152286 Hom.: 123 Cov.: 32 AF XY: 0.0197 AC XY: 1470 AN XY: 74482

African (AFR) AF: 0.0713 AC: 2963 AN: 41542

American (AMR) AF: 0.00706 AC: 108 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00195 AC: 133 AN: 68036

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00704 Hom.: 61

Bravo AF: 0.0242

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0642 AC: 255

ESP6500EA AF: 0.000958 AC: 8

ExAC AF: 0.00702 AC: 849

EpiCase AF: 0.00175

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.7
DANN	Benign	0.76
DEOGEN2	Benign	0.0010	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.99
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.043
Sift	Benign	0.56	T
Sift4G	Benign	0.51	T
Polyphen		0.027	B
Vest4		0.26
MVP		0.093
MPC		0.31
ClinPred		0.0021	T
GERP RS		-3.5
Varity_R		0.021
gMVP		0.29
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35254980; hg19: chr6-24848345;