rs144817385
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_206933.4(USH2A):āc.6998T>Cā(p.Val2333Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00026 ( 0 hom., cov: 32)
Exomes š: 0.00014 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 7.32
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.021000445).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.6998T>C | p.Val2333Ala | missense_variant | 37/72 | ENST00000307340.8 | NP_996816.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.6998T>C | p.Val2333Ala | missense_variant | 37/72 | 1 | NM_206933.4 | ENSP00000305941 | P1 | |
USH2A | ENST00000674083.1 | c.6998T>C | p.Val2333Ala | missense_variant | 37/73 | ENSP00000501296 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000402 AC: 101AN: 251046Hom.: 0 AF XY: 0.000339 AC XY: 46AN XY: 135690
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GnomAD4 exome AF: 0.000140 AC: 205AN: 1461480Hom.: 0 Cov.: 31 AF XY: 0.000131 AC XY: 95AN XY: 727046
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GnomAD4 genome AF: 0.000263 AC: 40AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2021 | Identified with other USH2A variants in individuals with hearing loss and/or retinitis pigmentosa in published literature (Sun et al., 2018; Ng et al., 2019; Xu et al., 2014; Yuan Y et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31541171, 31054281, 29625443, 24938718, 30948794) - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 12, 2018 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 30, 2017 | p.Val233Ala in exon 37 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified in 0.46% (87/18850) of East Asian chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org/; dbSNP rs144817385). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at