rs551424240
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_206933.4(USH2A):c.1582G>A(p.Asp528Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 4.79
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_206933.4
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1582G>A | p.Asp528Asn | missense_variant | 9/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1582G>A | p.Asp528Asn | missense_variant | 9/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1582G>A | p.Asp528Asn | missense_variant | 9/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1582G>A | p.Asp528Asn | missense_variant | 9/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1582G>A | p.Asp528Asn | missense_variant | 9/73 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151974Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250990Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135622
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461630Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727128
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Usher syndrome type 2A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 12, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 24, 2014 | The p.Asp528Asn variant in USH2A has not been previously reported in individuals with hearing loss but has been identified in 3/122780 chromosomes by the Exome Aggregation consortium (ExAC, http://exac.broadinstitute.org). Although this var iant was seen in the general population, its frequency is not high enough to rul e out a pathogenic role. The aspartic acid (Asp) residue at position 528 is mode rately conserved in mammals and evolutionary distant species, but two mammals (s quirrel and Cape golden mole) carry Asparagine (Asn), raising the possibility th at this change may be tolerated. Additional computational prediction tools do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the in p.Asp528Asn variant is uncertain. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 08, 2017 | - - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;T
Polyphen
D;P
Vest4
MutPred
Loss of disorder (P = 0.1786);Loss of disorder (P = 0.1786);
MVP
MPC
ClinPred
D
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