chr6-24818557-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001286445.3(RIPOR2):​c.2937T>A​(p.Ala979Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A979A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RIPOR2 NM_001286445.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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):

• autosomal recessive nonsyndromic hearing loss 104

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

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 21

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	NM_001286445.3	MANE Select	c.2937T>A	p.Ala979Ala	synonymous	Exon 20 of 22	NP_001273374.1
	RIPOR2	NM_014722.5		c.3000T>A	p.Ala1000Ala	synonymous	Exon 21 of 23	NP_055537.2
	RIPOR2	NM_001346031.2		c.2850T>A	p.Ala950Ala	synonymous	Exon 20 of 22	NP_001332960.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPOR2	ENST00000643898.2	MANE Select	c.2937T>A	p.Ala979Ala	synonymous	Exon 20 of 22	ENSP00000494268.2
	RIPOR2	ENST00000259698.9	TSL:1	c.3000T>A	p.Ala1000Ala	synonymous	Exon 21 of 23	ENSP00000259698.4
	RIPOR2	ENST00000613507.4	TSL:5	c.3000T>A	p.Ala1000Ala	synonymous	Exon 21 of 23	ENSP00000482957.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688996

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 35630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.00 AC: 0 AN: 35708

South Asian (SAS) AF: 0.00 AC: 0 AN: 78844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077100

Other (OTH) AF: 0.00 AC: 0 AN: 57870

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.3
DANN	Benign	0.57
PhyloP100		-0.073

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;