17-74922998-T-G

Variant names:

• chr17-74922998-T-G
• rs1405879054
• ENST00000580223.2:c.-267T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000580223.2(OTOP2):​c.-267T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTOP2 ENST00000580223.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• Publications: 0 publications found

Genes affected

OTOP2 (HGNC:19657): (otopetrin 2) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USH1G Gene-Disease associations (from GenCC):

• Usher syndrome type 1G

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000580223.2. 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
	USH1G	NM_173477.5	MANE Select	c.76A>C	p.Asn26His	missense	Exon 1 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.-181A>C		5_prime_UTR	Exon 1 of 3	NP_001269418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOP2	ENST00000580223.2	TSL:1	c.-267T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000463837.2	A0A6E1ZAN8
	USH1G	ENST00000614341.5	TSL:1 MANE Select	c.76A>C	p.Asn26His	missense	Exon 1 of 3	ENSP00000480279.1	Q495M9
	OTOP2	ENST00000580223.2	TSL:1	c.-267T>G		5_prime_UTR	Exon 1 of 5	ENSP00000463837.2	A0A6E1ZAN8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1417968 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700626

African (AFR) AF: 0.00 AC: 0 AN: 32564

American (AMR) AF: 0.00 AC: 0 AN: 38928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25394

East Asian (EAS) AF: 0.00 AC: 0 AN: 37470

South Asian (SAS) AF: 0.00 AC: 0 AN: 80992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088302

Other (OTH) AF: 0.00 AC: 0 AN: 58568

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Benign	0.83
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.0
PrimateAI	Uncertain	0.79	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.42		Loss of catalytic residue at N26 (P = 0.096)
MVP		0.62
ClinPred		0.88	D
GERP RS		4.1
PromoterAI		-0.045	Neutral
Varity_R		0.79
gMVP		0.83
Mutation Taster		=37/63	disease causing

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: rs1405879054; hg19: chr17-72919093;