rs41302239

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_206933.4(USH2A):​c.5858C>G​(p.Ala1953Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000763 in 1,613,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00076 ( 3 hom. )

Consequence

USH2A
NM_206933.4 missense, splice_region

Scores

7
12
Splicing: ADA: 0.9693
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:15B:5

Conservation

PhyloP100: 4.27
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a domain Fibronectin type-III 5 (size 86) in uniprot entity USH2A_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_206933.4
BP4
Computational evidence support a benign effect (MetaRNN=0.06280768).
BS2
High Homozygotes in GnomAdExome4 at 3 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 Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.5858C>G p.Ala1953Gly missense_variant, splice_region_variant 30/72 ENST00000307340.8 NP_996816.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.5858C>G p.Ala1953Gly missense_variant, splice_region_variant 30/721 NM_206933.4 ENSP00000305941 P1O75445-1
USH2AENST00000674083.1 linkuse as main transcriptc.5858C>G p.Ala1953Gly missense_variant, splice_region_variant 30/73 ENSP00000501296 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.000815
AC:
124
AN:
152168
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00223
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00103
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000844
AC:
212
AN:
251114
Hom.:
0
AF XY:
0.000899
AC XY:
122
AN XY:
135714
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.00104
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.000882
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00112
Gnomad OTH exome
AF:
0.00229
GnomAD4 exome
AF:
0.000758
AC:
1108
AN:
1461564
Hom.:
3
Cov.:
31
AF XY:
0.000795
AC XY:
578
AN XY:
727090
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00121
Gnomad4 ASJ exome
AF:
0.000153
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000881
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000740
Gnomad4 OTH exome
AF:
0.00144
GnomAD4 genome
AF:
0.000808
AC:
123
AN:
152286
Hom.:
1
Cov.:
32
AF XY:
0.000806
AC XY:
60
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00222
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00103
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000993
Hom.:
0
Bravo
AF:
0.000941
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000791
AC:
96
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00245
EpiControl
AF:
0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:15Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:7Benign:2
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 11, 2023- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2022This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1953 of the USH2A protein (p.Ala1953Gly). This variant is present in population databases (rs41302239, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa, retinal dystrophy, and Usher syndrome (PMID: 28041643, 28981474, 29142287). ClinVar contains an entry for this variant (Variation ID: 48546). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJul 25, 2019- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024USH2A: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 03, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 03, 2020This variant is associated with the following publications: (PMID: 24944099, 27145477, 26868535, 28981474, 28041643, 20507924, 33576794) -
Usher syndrome type 2A Pathogenic:1Uncertain:3Benign:1
Likely benign, criteria provided, single submitterclinical testingAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalFeb 11, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaNov 28, 2019This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,PP3. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Dec 31, 2019- -
Pathogenic, criteria provided, single submitterresearchLaboratory of Prof. Karen Avraham, Tel Aviv UniversityAug 20, 2024The p.(Ala1953Gly) is a known recessive variant based on PMID: 20507924. It was detected in an hearing impaired individual with a sloping audiogram, normal-to-profound HL. -
Retinal dystrophy Uncertain:2
Uncertain significance, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Uncertain significance, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 28, 2019The p.Ala1953Gly variant in USH2A has been identified in several individuals with hearing loss, retinitis pigmentosa, and Usher syndrome but has been identified in 0.1% (144/128948) of European chromosomes (http://gnomad.broadinstitute.org). This frequency suggests that the variant may not be pathogenic. Consistent with this, three individuals tested by our laboratory had alternate genetic explanations of their disease, including one individual who was homozygous for the p. Ala1953Gly variant but harbored another homozygous pathogenic USH2A variant. ACMG/AMP criteria applied: BS1_Supporting, BP2, BP5. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 08, 2022Variant summary: USH2A c.5858C>G (p.Ala1953Gly) results in a non-conservative amino acid change in 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 0.00084 in 251114 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00084 vs 0.011), allowing no conclusion about variant significance. c.5858C>G has been reported in the literature as a heterozygous genotype in combination with other heterozygous variants in the USH2A gene without phase clearly specified in probands with Retinitis Pigmentosa (RP), Retinal Dystrophies (RD), Pericentral Scotoma, and a reported diagnosis of Usher syndrome (example, Chebil_2016, Comander_2017, Carss_2017, Eandi_2017, Colombo_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=10). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
USH2A-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 03, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.79
T
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.063
T
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
0.87
D;D
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.13
Sift
Benign
0.046
D
Sift4G
Uncertain
0.044
D
Polyphen
1.0
D
Vest4
0.26
MVP
0.92
MPC
0.19
ClinPred
0.075
T
GERP RS
5.6
Varity_R
0.11
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Benign
0.67
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41302239; hg19: chr1-216243634; API