17-74922986-C-T

Position:

• chr17-74922986-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000580223(OTOP2):​c.-279C>T 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 0.00000142 in 1,410,846 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 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5	c.88G>A	p.Glu30Lys	missense_variant	1/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.-169G>A		5_prime_UTR_variant	1/3		NP_001269418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOP2	ENST00000580223	c.-279C>T		5_prime_UTR_premature_start_codon_gain_variant	1/5	1		ENSP00000463837.2
USH1G	ENST00000614341.5	c.88G>A	p.Glu30Lys	missense_variant	1/3	1	NM_173477.5	ENSP00000480279.1
OTOP2	ENST00000580223	c.-279C>T		5_prime_UTR_variant	1/5	1		ENSP00000463837.2
USH1G	ENST00000579243.1	n.88G>A		non_coding_transcript_exon_variant	1/3	2		ENSP00000462568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410846 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 696584

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.22e-7

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.88G>A (p.E30K) alteration is located in exon 1 (coding exon 1) of the USH1G gene. This alteration results from a G to A substitution at nucleotide position 88, causing the glutamic acid (E) at amino acid position 30 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.40		Gain of ubiquitination at E30 (P = 0.0162);
MVP		0.48
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.60
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-72919081;