chr1-216247062-C-A

Position:

chr1-216247062-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_206933.4(USH2A):c.2332G>T(p.Asp778Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,902 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). Synonymous variant affecting the same amino acid position (i.e. D778D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 4.59

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.

PM1

In a domain Laminin EGF-like 5 (size 47) in uniprot entity USH2A_HUMAN there are 20 pathogenic changes around while only 2 benign (91%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

PP5

Variant 1-216247062-C-A is Pathogenic according to our data. Variant chr1-216247062-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178583.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=4}. Variant chr1-216247062-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.2332G>T	p.Asp778Tyr	missense_variant	13/72	ENST00000307340.8
USH2A	NM_007123.6 linkuse as main transcript	c.2332G>T	p.Asp778Tyr	missense_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.2332G>T	p.Asp778Tyr	missense_variant	13/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.2332G>T	p.Asp778Tyr	missense_variant	13/21	1			O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.2332G>T	p.Asp778Tyr	missense_variant	13/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250894

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135554

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000868

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000131

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.000435

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31904091, 31736247, 17085681, 26969326, 32637036, 25649381) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 778 of the USH2A protein (p.Asp778Tyr). This variant is present in population databases (rs142898216, gnomAD 0.05%). This missense change has been observed in individual(s) with Usher syndrome or non-syndromic retinal disease (PMID: 17085681, 25649381, 26969326; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 178583). 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	The USH2A c.2332G>T; p.Asp778Tyr variant (rs142898216; ClinVar Variation ID: 178583) has been previously observed in patients with clinical features of Usher syndrome (US) or retinitis pigmentosa (RP). One patient with US found to be homozygous for this variant, while one US and one RP patient were found to carry this variant in a presumed transheterozygous configuration with other established pathogenic variants in USH2A (Aller 2006, Lenassi 2015, Sloan-Heggen 2016). This variants is rare in the general population, though it is found at higher frequencies is African Americans in in the Genome Aggregation Database (0.056% MAF; 14 out of 24,968 chromosomes, including 1 homozygous individual). The aspartic acid at codon 778 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.598). Based on the available information, the clinical significance of this variant is uncertain. References: Aller et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006 Nov;43(11):e55. PMID: 17085681 Lenassi et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27. PMID: 25649381 Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450. PMID: 26969326 -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 14, 2021

Variant summary: USH2A c.2332G>T (p.Asp778Tyr) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250894 control chromosomes in the gnomAD database, including 1 homozygote. c.2332G>T has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome or retinal disease (examples: Aller_2006, Sloan-Heggen_2016, Zenteno_2019, and McGowan_2020), as well as a homozygous individual with normal hearing and nyctalopia (Lenassi_2015). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and as a variant of uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 26, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp778Tyr variant in USH2A has been reported in 1 Spanish individual with Usher syndrome who also carried a known pathogenic variant (Aller 2006). This variant has been identified in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs142898216); howev er this frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools suggest that the p.Asp778Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the p.Asp778Tyr variant is uncertain. -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 03, 2021

NM_206933.2(USH2A):c.2332G>T(D778Y) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. D778Y has been observed in cases with relevant disease (PMID: 31736247, 25649381, 17085681, 26969326). Functional assessments of this variant are not available in the literature. D778Y has been observed in population frequency databases (gnomAD: AFR 0.05%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.2332G>T(D778Y) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

4.4

H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.96

MVP

0.97

MPC

0.25

ClinPred

0.84

GERP RS

6.1

Varity_R

0.67

gMVP

0.93

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