rs10864219

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.6506T>C(p.Ile2169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,609,012 control chromosomes in the GnomAD database, including 220,928 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20321 hom., cov: 32)

Exomes 𝑓: 0.52 ( 200607 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.37

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5664968E-6).

BP6

Variant 1-215999038-A-G is Benign according to our data. Variant chr1-215999038-A-G is described in ClinVar as [Benign]. Clinvar id is 48562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215999038-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.6506T>C	p.Ile2169Thr	missense_variant	34/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.6506T>C	p.Ile2169Thr	missense_variant	34/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6506T>C	p.Ile2169Thr	missense_variant	34/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.510

AC:

77324

AN:

151720

Hom.:

20294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.430

Gnomad AMI

AF:

0.684

Gnomad AMR

AF:

0.558

Gnomad ASJ

AF:

0.500

Gnomad EAS

AF:

0.842

Gnomad SAS

AF:

0.612

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.510

Gnomad NFE

AF:

0.502

Gnomad OTH

AF:

0.509

GnomAD3 exomes

AF:

0.563

AC:

140654

AN:

249906

Hom.:

41171

AF XY:

0.558

AC XY:

75437

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.433

Gnomad AMR exome

AF:

0.670

Gnomad ASJ exome

AF:

0.490

Gnomad EAS exome

AF:

0.841

Gnomad SAS exome

AF:

0.598

Gnomad FIN exome

AF:

0.572

Gnomad NFE exome

AF:

0.500

Gnomad OTH exome

AF:

0.539

GnomAD4 exome

AF:

0.518

AC:

755422

AN:

1457174

Hom.:

200607

Cov.:

AF XY:

0.520

AC XY:

377298

AN XY:

725068

show subpopulations

Gnomad4 AFR exome

AF:

0.432

Gnomad4 AMR exome

AF:

0.664

Gnomad4 ASJ exome

AF:

0.496

Gnomad4 EAS exome

AF:

0.865

Gnomad4 SAS exome

AF:

0.595

Gnomad4 FIN exome

AF:

0.568

Gnomad4 NFE exome

AF:

0.495

Gnomad4 OTH exome

AF:

0.523

GnomAD4 genome

AF:

0.510

AC:

77394

AN:

151838

Hom.:

20321

Cov.:

AF XY:

0.518

AC XY:

38426

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.430

Gnomad4 AMR

AF:

0.558

Gnomad4 ASJ

AF:

0.500

Gnomad4 EAS

AF:

0.843

Gnomad4 SAS

AF:

0.613

Gnomad4 FIN

AF:

0.582

Gnomad4 NFE

AF:

0.502

Gnomad4 OTH

AF:

0.511

Alfa

AF:

0.505

Hom.:

43586

Bravo

AF:

0.511

TwinsUK

AF:

0.499

AC:

1849

ALSPAC

AF:

0.495

AC:

1906

ESP6500AA

AF:

0.438

AC:

1932

ESP6500EA

AF:

0.503

AC:

4323

ExAC

AF:

0.556

AC:

67525

Asia WGS

AF:

0.699

AC:

2430

AN:

3478

EpiCase

AF:

0.496

EpiControl

AF:

0.493

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -

Usher syndrome type 2A

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

0.11

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.057

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0000016

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

REVEL

Benign

0.11

Sift

Benign

0.24

Sift4G

Uncertain

0.054

Polyphen

0.094

Vest4

0.056

MPC

0.037

ClinPred

0.017

GERP RS

5.8

Varity_R

0.10

gMVP

0.20

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