rs35818432
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting
The NM_206933.4(USH2A):āc.1663C>Gā(p.Leu555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000972 in 1,613,940 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.00084 ( 1 hom., cov: 32)
Exomes š: 0.00099 ( 2 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
4
6
9
Clinical Significance
Conservation
PhyloP100: 3.10
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 -4 ACMG points.
PM1
?
In a domain Laminin EGF-like 1 (size 56) in uniprot entity USH2A_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in NM_206933.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.035342634).
BP6
?
Variant 1-216292352-G-C is Benign according to our data. Variant chr1-216292352-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48472.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=4, Uncertain_significance=6}. Variant chr1-216292352-G-C is described in Lovd as [Likely_benign].
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.1663C>G | p.Leu555Val | missense_variant | 10/72 | ENST00000307340.8 | |
USH2A | NM_007123.6 | c.1663C>G | p.Leu555Val | missense_variant | 10/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.1663C>G | p.Leu555Val | missense_variant | 10/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.1663C>G | p.Leu555Val | missense_variant | 10/21 | 1 | |||
USH2A | ENST00000674083.1 | c.1663C>G | p.Leu555Val | missense_variant | 10/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000841 AC: 128AN: 152182Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00129 AC: 323AN: 251082Hom.: 2 AF XY: 0.00150 AC XY: 203AN XY: 135706
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GnomAD4 exome AF: 0.000985 AC: 1440AN: 1461640Hom.: 2 Cov.: 30 AF XY: 0.00109 AC XY: 792AN XY: 727128
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GnomAD4 genome ? AF: 0.000840 AC: 128AN: 152300Hom.: 1 Cov.: 32 AF XY: 0.000819 AC XY: 61AN XY: 74472
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:6
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 25262649, 22995991, 14676276, 22004887, 21228398, 11311042, 27884173, 21569298, 29068140, 30245029, 31456290, 32707200) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 17, 2022 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | USH2A: BP4, BS2 - |
Usher syndrome type 2A Uncertain:2Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 02, 2017 | p.Leu555Val in exon 10 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified 0.2% (24/10136) of Ashkenazi Jewish c hromosomes and in 0.2% (212/126366) of European chromosomes including 1 homozygo te by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35818432). It has been reported in cis with another pathogenic variant in USH2A (Jaijo 2009, Vozzi 2011). A study has shown that the variant does not i mpact protein function (Bhattacharya 2004). - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 10, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2023 | Variant summary: USH2A c.1663C>G (p.Leu555Val) results in a conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 1613940 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00097 vs 0.011), allowing no conclusion about variant significance. c.1663C>G has been reported in the literature in individuals affected with USH2A related conditions without strong evidence for causality (examples: Leory_2001, Colombo_2022, Karali_2022). One publication reported an individual affected with Usher syndrome with this variant and a second pathogenic variant c.1841-2A>G in homozygous state, supporting a benign role for this variant (example: Jaijo_2010). Multiple reports have classified this variant as benign (examples: Shearer_2014 and Azaiez_2018). At least one publication reports experimental evidence that this variant had no effect on usherin/collagen IV binding (example: Bhattacharya_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11311042, 14676276, 19683999, 21569298, 25262649, 30245029, 29068140, 34781295, 36460718). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as benign/likely benign (n=6), VUS (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Retinitis pigmentosa Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The USH2A c.1663C>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, BP2. Based on this evidence we have classified this variant as Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;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