rs58257972

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ser5188Gly variant in the USH2A gene is 6.8% (2200/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143409/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0060 ( 24 hom., cov: 32)
Exomes 𝑓: 0.0092 ( 345 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

1
6
11

Clinical Significance

Benign reviewed by expert panel B:14

Conservation

PhyloP100: 5.55
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 Benign. Variant got -8 ACMG points.

BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkc.15562A>G p.Ser5188Gly missense_variant 72/72 ENST00000307340.8 NP_996816.3 O75445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.15562A>G p.Ser5188Gly missense_variant 72/721 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.15634A>G p.Ser5212Gly missense_variant 73/73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.00603
AC:
918
AN:
152172
Hom.:
24
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00111
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00589
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.0291
Gnomad SAS
AF:
0.0702
Gnomad FIN
AF:
0.00433
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00342
Gnomad OTH
AF:
0.00527
GnomAD3 exomes
AF:
0.0125
AC:
3146
AN:
251432
Hom.:
97
AF XY:
0.0156
AC XY:
2114
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.000861
Gnomad AMR exome
AF:
0.00173
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.0186
Gnomad SAS exome
AF:
0.0712
Gnomad FIN exome
AF:
0.00300
Gnomad NFE exome
AF:
0.00376
Gnomad OTH exome
AF:
0.00896
GnomAD4 exome
AF:
0.00917
AC:
13402
AN:
1461784
Hom.:
345
Cov.:
31
AF XY:
0.0108
AC XY:
7872
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.000687
Gnomad4 AMR exome
AF:
0.00215
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0493
Gnomad4 SAS exome
AF:
0.0684
Gnomad4 FIN exome
AF:
0.00253
Gnomad4 NFE exome
AF:
0.00423
Gnomad4 OTH exome
AF:
0.00924
GnomAD4 genome
AF:
0.00604
AC:
920
AN:
152290
Hom.:
24
Cov.:
32
AF XY:
0.00744
AC XY:
554
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00111
Gnomad4 AMR
AF:
0.00589
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.0293
Gnomad4 SAS
AF:
0.0704
Gnomad4 FIN
AF:
0.00433
Gnomad4 NFE
AF:
0.00343
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00437
Hom.:
4
Bravo
AF:
0.00434
TwinsUK
AF:
0.00458
AC:
17
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00337
AC:
29
ExAC
AF:
0.0135
AC:
1633
Asia WGS
AF:
0.0480
AC:
168
AN:
3478
EpiCase
AF:
0.00431
EpiControl
AF:
0.00302

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:5
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 16, 2020- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 16, 2019This variant is associated with the following publications: (PMID: 25356976) -
not specified Benign:4
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 18, 2022- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 21, 2014- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 19, 2010- -
Usher syndrome type 2A Benign:2
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Usher syndrome Benign:1
Benign, reviewed by expert panelcurationClinGen Hearing Loss Variant Curation Expert PanelSep 17, 2018The filtering allele frequency of the p.Ser5188Gly variant in the USH2A gene is 6.8% (2200/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 10, 2022- -
Retinal dystrophy Benign:1
Benign, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.82
T
MetaRNN
Benign
0.0023
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.075
Sift
Benign
0.065
T
Sift4G
Uncertain
0.013
D
Polyphen
0.91
P
Vest4
0.13
MPC
0.065
ClinPred
0.023
T
GERP RS
5.9
Varity_R
0.20
gMVP
0.18

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

LitVar

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

Other links and lift over

dbSNP: rs58257972; hg19: chr1-215799170; API