1-215798983-G-C

Position:

chr1-215798983-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_206933.4(USH2A):c.9882C>G(p.Cys3294Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C3294F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 5.00

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]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-215798984-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1518640.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 1-215798983-G-C is Pathogenic according to our data. Variant chr1-215798983-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438036.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3, Likely_pathogenic=1}. Variant chr1-215798983-G-C is described in Lovd as [Pathogenic]. Variant chr1-215798983-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9882C>G	p.Cys3294Trp	missense_variant	50/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.9882C>G	p.Cys3294Trp	missense_variant	50/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9882C>G	p.Cys3294Trp	missense_variant	50/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152152

Hom.:

Cov.:

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251252

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135778

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:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727212

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:

0.0000405

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32646269, 36819107, 31964843, 35266249, 36007554, 34031601, Bensinger[thesis]2021, 33749171, 34906470, 24043777, 25412400, 28041643) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 3294 of the USH2A protein (p.Cys3294Trp). This variant is present in population databases (rs749228276, gnomAD 0.008%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 24043777, 28041643, 28130426). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -

Retinitis pigmentosa 39

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.9882C>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, PP1. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Cys3294Trp variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP1. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 20, 2024

- -

Usher syndrome type 2A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 16, 2021

NM_206933.2(USH2A):c.9882C>G(C3294W) is a missense variant classified as likely pathogenic in the context of USH2A-related disorders. Please note that C3294W is associated with retinitis pigmentosa. C3294W has been observed in cases with relevant disease (PMID: 24043777, 28041643, 25412400, 28130426, 32646269, 34031601). Functional assessments of this variant are not available in the literature. C3294W has been observed in population frequency databases (gnomAD: NFE 0.009%). In summary, NM_206933.2(USH2A):c.9882C>G(C3294W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.048

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-8.3

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.90

MPC

0.26

ClinPred

0.99

GERP RS

4.9

Varity_R

0.94

gMVP

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over