1-216323590-C-G

Position:

chr1-216323590-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_206933.4(USH2A):c.1434G>C(p.Glu478Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,512 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. E478E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 18 hom., cov: 31)

Exomes 𝑓: 0.016 ( 235 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 0.0430

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 Benign. Variant got -11 ACMG points.

PM1

In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 107 pathogenic changes around while only 17 benign (86%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.007865071).

BP6

Variant 1-216323590-C-G is Benign according to our data. Variant chr1-216323590-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48437.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=8}. Variant chr1-216323590-C-G is described in Lovd as [Likely_pathogenic]. Variant chr1-216323590-C-G is described in Lovd as [Benign]. Variant chr1-216323590-C-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1920/152048) while in subpopulation NFE AF= 0.0187 (1270/67972). AF 95% confidence interval is 0.0178. There are 18 homozygotes in gnomad4. There are 921 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.1434G>C	p.Glu478Asp	missense_variant	8/72	ENST00000307340.8
USH2A	NM_007123.6 linkuse as main transcript	c.1434G>C	p.Glu478Asp	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.1434G>C	p.Glu478Asp	missense_variant	8/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.1434G>C	p.Glu478Asp	missense_variant	8/21	1			O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.1434G>C	p.Glu478Asp	missense_variant	8/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1920

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00353

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.0121

AC:

3034

AN:

250826

Hom.:

AF XY:

0.0119

AC XY:

1607

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00811

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.0169

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0165

AC:

24111

AN:

1461464

Hom.:

235

Cov.:

AF XY:

0.0163

AC XY:

11829

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.00882

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00243

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0190

Gnomad4 OTH exome

AF:

0.0143

GnomAD4 genome

AF:

0.0126

AC:

1920

AN:

152048

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

921

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00352

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.0233

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.0187

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0157

AC:

135

ExAC

AF:

0.0118

AC:

1437

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0171

EpiControl

AF:

0.0179

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2022	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 2A

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;M

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.044

Sift

Benign

0.15

T;T

Sift4G

Uncertain

0.037

D;T

Polyphen

0.10

B;B

Vest4

0.076

MutPred

0.65

Loss of ubiquitination at K481 (P = 0.1778);Loss of ubiquitination at K481 (P = 0.1778);

MPC

0.12

ClinPred

0.016

GERP RS

0.84

Varity_R

0.13

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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