chr1-215888472-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.8177G>A variant in USH2A is a missense variant predicted to cause substitution of glycine to glutamic acid at amino acid 2726. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/111282 alleles) in the European population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.406, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. The variant has been detected in heterozygosity without a second variant in one female proband from the Laboratory of Molecular Medicine with mild to moderate sensorineural hearing loss and other syndromic features (SCV000206052.5). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 9/26/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA184631/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

5
8
6

Clinical Significance

Uncertain significance reviewed by expert panel U:7

Conservation

PhyloP100: 2.80
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.8177G>A p.Gly2726Glu missense_variant Exon 41 of 72 ENST00000307340.8 NP_996816.3 O75445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.8177G>A p.Gly2726Glu missense_variant Exon 41 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.8177G>A p.Gly2726Glu missense_variant Exon 41 of 73 ENSP00000501296.1 O75445-3
ENSG00000229242ENST00000414995.1 linkn.60+1831C>T intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250974
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135632
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1461528
Hom.:
0
Cov.:
32
AF XY:
0.0000220
AC XY:
16
AN XY:
727086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000625
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:2
Feb 06, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Gly2726Glu variant in USH2A has not been previously reported in individuals with hearing loss or in large population studies. The amino acid residue at this position is not conserved in several species suggesting that variants at this p osition may be tolerated; however, computational analyses (AlignGVGD, PolyPhen2, and SIFT) predict that the variant may impact the protein. In summary, addition al information is needed to fully assess the clinical significance of this varia nt. -

Aug 24, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2
May 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2726 of the USH2A protein (p.Gly2726Glu). This variant is present in population databases (rs549796389, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 179542). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Feb 02, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2 -

Usher syndrome Uncertain:1
Sep 26, 2023
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The c.8177G>A variant in USH2A is a missense variant predicted to cause substitution of glycine to glutamic acid at amino acid 2726. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/111282 alleles) in the European population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.406, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. The variant has been detected in heterozygosity without a second variant in one female proband from the Laboratory of Molecular Medicine with mild to moderate sensorineural hearing loss and other syndromic features (SCV000206052.5). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 9/26/2023) -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Jul 27, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A Uncertain:1
Mar 27, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.080
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T
Eigen
Uncertain
0.28
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.75
T
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Benign
-0.62
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.9
D
REVEL
Uncertain
0.41
Sift
Uncertain
0.0050
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.51
MutPred
0.76
Loss of catalytic residue at V2727 (P = 0.058);
MVP
0.95
MPC
0.23
ClinPred
0.97
D
GERP RS
3.8
Varity_R
0.53
gMVP
0.61

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: rs549796389; hg19: chr1-216061814; API