1-215999038-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:15

Conservation

PhyloP100: 2.37

Publications

52 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.6506T>C	p.Ile2169Thr	missense_variant	Exon 34 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.6506T>C	p.Ile2169Thr	missense_variant	Exon 34 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.6506T>C	p.Ile2169Thr	missense_variant	Exon 34 of 73			ENSP00000501296.1		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

GnomAD2 exomes

AF:

0.563

AC:

140654

AN:

249906

AF XY:

0.558

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 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

African (AFR)

AF:

0.432

AC:

14410

AN:

33334

American (AMR)

AF:

0.664

AC:

29581

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

12913

AN:

26052

East Asian (EAS)

AF:

0.865

AC:

34241

AN:

39564

South Asian (SAS)

AF:

0.595

AC:

51173

AN:

85970

European-Finnish (FIN)

AF:

0.568

AC:

30309

AN:

53336

Middle Eastern (MID)

AF:

0.509

AC:

2902

AN:

5706

European-Non Finnish (NFE)

AF:

0.495

AC:

548408

AN:

1108454

Other (OTH)

AF:

0.523

AC:

31485

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

16338

32677

49015

65354

81692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.510

AC:

77394

AN:

151838

Hom.:

20321

Cov.:

AF XY:

0.518

AC XY:

38426

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.430

AC:

17789

AN:

41398

American (AMR)

AF:

0.558

AC:

8503

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

1737

AN:

3472

East Asian (EAS)

AF:

0.843

AC:

4351

AN:

5160

South Asian (SAS)

AF:

0.613

AC:

2955

AN:

4818

European-Finnish (FIN)

AF:

0.582

AC:

6144

AN:

10552

Middle Eastern (MID)

AF:

0.521

AC:

152

AN:

292

European-Non Finnish (NFE)

AF:

0.502

AC:

34064

AN:

67894

Other (OTH)

AF:

0.511

AC:

1077

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1906

3811

5717

7622

9528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.504

Hom.:

68469

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Jun 26, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 10, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

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

PhyloP100

2.4

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

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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1-215999038-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over